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Omae T, Omori Y, Makihara Y, Yamanegi K, Hanawa S, Yoshikawa K, Noguchi K, Kishimoto H. Mechanism of Tumor Budding in Patient-Derived Metachronous Oral Primary Squamous Cell Carcinoma Cell Lines. Int J Mol Sci 2025; 26:3347. [PMID: 40244200 PMCID: PMC11989605 DOI: 10.3390/ijms26073347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/18/2025] Open
Abstract
Tumor budding (TB) occurs at the deepest site of tumor invasion and is a significant prognostic indicator of cervical metastasis in oral squamous cell carcinoma (OSCC). The mechanism of TB, however, remains unclear. This study investigated the roles of the tumor microenvironment and partial epithelial-mesenchymal transition (p-EMT) in TB expression using molecular and cellular physiological analyses. We established oral metachronous carcinoma cell lines (gingival carcinoma: 020, tongue carcinoma with high TB expression: 020G) from two cancers with pathologically different TB in the same patient and subjected them to exome analysis to detect gene mutations related to carcinogenesis and malignancy. Differences in EMT expression induced by transforming growth factor-β (TGF-β) between 020 and 020G were analyzed by Western blotting and reverse transcription polymerase chain reaction, and TGF-β-induced changes in cell morphology, proliferation, migration, and invasive ability were also examined. TGF-β expression was observed in the deepest tumor invasion microenvironment. TGF-β also induced the expression of several p-EMT markers and increased the migration and invasive abilities of 020G compared with 020 cells. In conclusion, TGF-β in the deep-tumor microenvironment can induce p-EMT in tumor cells, expressed as TB.
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Affiliation(s)
- Takayuki Omae
- Department of Oral and Maxillofacial Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan; (T.O.); (Y.O.); (Y.M.); (S.H.); (K.Y.); (H.K.)
| | - Yuji Omori
- Department of Oral and Maxillofacial Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan; (T.O.); (Y.O.); (Y.M.); (S.H.); (K.Y.); (H.K.)
| | - Yuna Makihara
- Department of Oral and Maxillofacial Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan; (T.O.); (Y.O.); (Y.M.); (S.H.); (K.Y.); (H.K.)
| | - Koji Yamanegi
- Department of Pathology, School of Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan;
| | - Soutaro Hanawa
- Department of Oral and Maxillofacial Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan; (T.O.); (Y.O.); (Y.M.); (S.H.); (K.Y.); (H.K.)
| | - Kyohei Yoshikawa
- Department of Oral and Maxillofacial Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan; (T.O.); (Y.O.); (Y.M.); (S.H.); (K.Y.); (H.K.)
| | - Kazuma Noguchi
- Department of Oral and Maxillofacial Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan; (T.O.); (Y.O.); (Y.M.); (S.H.); (K.Y.); (H.K.)
| | - Hiromitsu Kishimoto
- Department of Oral and Maxillofacial Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan; (T.O.); (Y.O.); (Y.M.); (S.H.); (K.Y.); (H.K.)
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Kojima S, Kuribayashi N, Goda H, Nakashiro KI, Uchida D. Oral cancer driver gene mutations in oral potentially malignant disorders: clinical significance and diagnostic implications. Discov Oncol 2025; 16:174. [PMID: 39946003 PMCID: PMC11825417 DOI: 10.1007/s12672-025-01923-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
Oral potentially malignant disorders (OPMDs), such as oral lichen planus (OLP) and oral leukoplakia (OLK), are clinical conditions associated with the risk of developing oral squamous cell carcinoma; however, no standardized treatment guidelines exist. Mutations in specific genes, known as oral cancer driver gene mutations (ODGMs), are responsible for carcinogenesis. We aimed to analyze the ODGMs in OPMDs and investigate their clinical correlations. We investigated 41 cases of OPMDs, including OLP and OLK, and performed next-generation sequencing using a custom gene panel targeting whole exons of TP53, HRAS, PIK3CA, NOTCH1, CDKN2A, FBXW7, and BRAF. We detected ODGMs in four OLK cases and one OLP case. All ODGM-positive OLK cases were located in the tongue, a site associated with a higher risk of malignant transformation compared with those in other oral sites. Moreover, ODGMs were significantly associated with alcohol consumption. While there was a tendency for mutations to increase with higher grades, we found no significant correlation between the presence of ODGMs and oral epithelial dysplasia (OED) grade. Notably, in the case of OLP with ODGM, the lesion histopathologically developed OED during the follow-up period, indicating an increased risk of cancer development and that cases with identified ODGMs require early surgical excision. These findings suggest that ODGM analysis may predict the risk of cancer development in OPMDs that are difficult to diagnose using histopathological examination alone.
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Affiliation(s)
- Sayaka Kojima
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Nobuyuki Kuribayashi
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Hiroyuki Goda
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Koh-Ichi Nakashiro
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Daisuke Uchida
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
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Ichimura N, Urata Y, Kobayashi T, Ebata R, Matsumoto H, Hibi H. Mutational landscape of Japanese patients with oral squamous cell carcinoma from comprehensive genomic profiling tests. Oral Oncol 2024; 159:107079. [PMID: 39432990 DOI: 10.1016/j.oraloncology.2024.107079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/08/2024] [Accepted: 10/13/2024] [Indexed: 10/23/2024]
Abstract
OBJECTIVES Oral squamous cell carcinoma (OSCC) is the most common subtype of head and neck squamous cell carcinoma (HNSCC). Treatment options for OSCC are currently limited owing to the lack of identified therapeutic targets. In this study, we aimed to analyze the genomic profiles of Japanese patients with OSCC and compare them to those of patients with HNSCC to identify potential therapeutic targets. MATERIALS AND METHODS We extracted the clinical and genomic information of patients with OSCC (n = 242) and those with other HNSCC (n = 402) who underwent comprehensive genomic profiling tests under the National Health Insurance between June 2019 and April 2024 from the Center for Cancer Genomics and Therapeutics database. RESULTS The most frequent genomic alterations identified in OSCC were TP53 (85.5 %), followed by TERT (62.4 %), CDKN2A (41.3 %), FGF19 (24.9 %), and CCND1 (23.6 %). FGF19 and CCND1 were co-amplified, and CDKN2A and CDKN2B were co-deleted. The frequencies of TERT, HRAS, and CASP8 alterations were the highest in OSCC among all HNSCC subtypes. The frequency of EGFR alterations was substantially higher in adolescent and young adults than older patients with OSCC. Genes associated with genomic integrity and the RTK-RAS pathway were frequently altered in OSCC. CONCLUSION This study analyzed the genomic profiles of patients with OSCC in Japan and the genetic differences between OSCC and other HNSCC subtypes. This analysis offers insights into the development of personalized therapeutics for OSCC.
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Affiliation(s)
- Norihisa Ichimura
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Yusuke Urata
- Department of Oral and Maxillofacial Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Takeru Kobayashi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ryo Ebata
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroya Matsumoto
- Department of Oral and Maxillofacial Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Hideharu Hibi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Oral and Maxillofacial Surgery, Nagoya University Hospital, Nagoya, Japan
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Hsu C, Wen Y, Wang H, Hsieh C, Liao C, Lee L, Ng S, Lin C, Chen W, Lin J, Tsai Y, Lee S, Chien C, Hua C, Wang CP, Chen T, Terng S, Tsai C, Fan K, Yeh C, Lin C, Tsao C, Cheng N, Fang T, Huang S, Kang C, Lee L, Fang K, Wang Y, Lin W, Hsin L, Yen T, Liao C. Prognostic impact of bridge or neoadjuvant induction chemotherapy in patients with resected oral cavity cancer: A nationwide cohort study. Cancer Med 2024; 13:e70061. [PMID: 39101462 PMCID: PMC11299076 DOI: 10.1002/cam4.70061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 06/18/2024] [Accepted: 07/20/2024] [Indexed: 08/06/2024] Open
Abstract
BACKGROUND While surgery remains the primary treatment for oral squamous cell carcinoma (OCSCC), induction chemotherapy (IC) can be used as a bridging or neoadjuvant therapy. This nationwide study in Taiwan examines the survival outcomes of OCSCC patients who received IC before surgery. METHODS We analyzed data from 29,891 patients with OCSCC. Of these, 29,058 initially underwent surgery (OP group), whereas 833 received IC before surgery (IC + OP group). A propensity score (PS)-matched analysis (4, 1 ratio, 3260 vs. 815 patients) was performed considering tumor subsite, sex, age, Charlson comorbidity index, clinical T1-T4b tumors, clinical N0-3 disease, and clinical stage I-IV. RESULTS In the PS-matched cohort, the 5-year disease-specific survival (DSS) and overall survival (OS) rates were 65% and 57%, respectively. When comparing the OP and IC + OP groups, the 5-year DSS rates were 66% and 62%, respectively (p = 0.1162). Additionally, the 5-year OS rates were 57% and 56%, respectively (p = 0.9917). No significant intergroup differences in survival were observed for specific subgroups with cT4a tumors, cT4b tumors, cN3 disease, pT4b tumors, and pN3 disease. However, for patients with pT4a tumors, the OP group demonstrated superior 5-year outcomes compared to the IC + OP group, with a DSS of 62% versus 52% (p = 0.0006) and an OS of 53% versus 44% (p = 0.0060). Notably, patients with cT2-3, cN1, and c-Stage II disease in the IC + OP group were significantly more likely to achieve pT0-1 status (p < 0.05). CONCLUSIONS Following PS matching, the IC + OP group generally exhibited similar prognosis to the OP group. However, for pT4a tumors, the OP group showed superior 5-year outcomes. While IC may not universally improve survival, it could be advantageous for patients who respond positively to the treatment.
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Affiliation(s)
- Cheng‐Lung Hsu
- Department of Medical OncologyChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Yu‐Wen Wen
- Clinical Informatics and Medical Statistics Research CenterChang Gung UniversityTaoyuanTaiwan
- Division of Thoracic SurgeryChang Gung Memorial HospitalTaoyuanTaiwan
| | - Hung‐Ming Wang
- Department of Medical OncologyChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Chia‐Hsun Hsieh
- Department of Medical OncologyChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Chi‐Ting Liao
- Department of Medical OncologyChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Li‐Yu Lee
- Department of PathologyChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Shu‐Hang Ng
- Department of Diagnostic RadiologyChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Chien‐Yu Lin
- Department of Radiation OncologyChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Wen‐Cheng Chen
- Department of Radiation OncologyChang Gung Memorial HospitalChiayiTaiwan
| | - Jin‐Ching Lin
- Department of Radiation OncologyChanghua Christian HospitalChanghuaTaiwan
| | - Yao‐Te Tsai
- Department of Otorhinolaryngology‐Head and Neck SurgeryChang Gung Memorial HospitalChiayiTaiwan
| | - Shu‐Ru Lee
- Research Service Center for Health InformationChang Gung UniversityTaoyuanTaiwan
| | - Chih‐Yen Chien
- Department of Otolaryngology, Chang Gung Memorial Hospital Kaohsiung Medical CenterChang Gung University College of MedicineKaohsiungTaiwan
| | - Chun‐Hung Hua
- Department of OtorhinolaryngologyChina Medical University HospitalTaichungTaiwan
| | - Cheng Ping Wang
- Department of OtolaryngologyNational Taiwan University Hospital and College of MedicineTaipeiTaiwan
| | - Tsung‐Ming Chen
- Department of OtolaryngologyShuang Ho Hospital, Taipei Medical UniversityNew Taipei CityTaiwan
| | - Shyuang‐Der Terng
- Department of Head and Neck SurgeryKoo Foundation Sun Yat‐Sen Cancer CenterTaipeiTaiwan
| | - Chi‐Ying Tsai
- Department of Oral and Maxillofacial SurgeryChang Gung Memorial Hospital, Chang Gung UniversityTaoyuanTaiwan
| | - Kang‐Hsing Fan
- Department of Radiation OncologyNew Taipei Municipal TuCheng HospitalNew Taipei CityTaiwan
| | - Chih‐Hua Yeh
- Department of Diagnostic RadiologyChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Chih‐Hung Lin
- Department of Plastic and Reconstructive SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Chung‐Kan Tsao
- Department of Plastic and Reconstructive SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Nai‐Ming Cheng
- Department of Nuclear Medicine and Molecular Imaging CenterChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Tuan‐Jen Fang
- Department of Otorhinolaryngology, Head and Neck SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Shiang‐Fu Huang
- Department of Otorhinolaryngology, Head and Neck SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Chung‐Jan Kang
- Department of Otorhinolaryngology, Head and Neck SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Li‐Ang Lee
- Department of Otorhinolaryngology, Head and Neck SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Ku‐Hao Fang
- Department of Otorhinolaryngology, Head and Neck SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Yu‐Chien Wang
- Department of Otorhinolaryngology, Head and Neck SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Wan‐Ni Lin
- Department of Otorhinolaryngology, Head and Neck SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Li‐Jen Hsin
- Department of Otorhinolaryngology, Head and Neck SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Tzu‐Chen Yen
- Department of Nuclear Medicine and Molecular Imaging CenterChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
| | - Chun‐Ta Liao
- Department of Otorhinolaryngology, Head and Neck SurgeryChang Gung Memorial Hospital and Chang Gung UniversityTaoyuanTaiwan
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Ono S, Hirose K, Sukegawa S, Obata K, Masui M, Hasegawa K, Fujimura A, Shimada K, Nakamura S, Teramoto A, Hori Y, Morii E, Motooka D, Igawa T, Tanaka T, Nagatsuka H, Toyosawa S, Yamamoto H. Squamous cell carcinoma initially occurring on the tongue dorsum: a case series report with molecular analysis. Diagn Pathol 2024; 19:63. [PMID: 38650013 PMCID: PMC11034101 DOI: 10.1186/s13000-024-01487-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 04/13/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Squamous cell carcinoma (SCC) of the dorsum of the tongue is extremely rare, and it clinically resembles various benign lesions. Somatic mutations in TP53 and some driver genes were implicated in the development of SCC; however, the somatic genetic characteristics of dorsal tongue SCC remain unknown. With a detailed analysis of gene mutations in dorsal tongue SCC, we aimed to better understand its biology. METHODS Four cases of SCC initially occurring on the tongue dorsum were evaluated for clinical and histological findings and immunohistochemical expression of p53 and p16. Gene mutations were analyzed using next-generation sequencing with a custom panel of driver genes. RESULTS We retrospectively investigated 557 cases of tongue SCC, and only four cases of SCC initially occurred on the tongue dorsum. The four patients (cases 1-4) were one woman and three men with a mean age of 53.75 years (range: 15-74 years). Histological analysis revealed well-differentiated SCC. Through molecular analysis, we identified pathogenic somatic mutations, namely, TP53 p.C176F (c.527G > T) in case 3 and TP53 p.R282W (c.844 C > T) in case 4. No pathogenic variants were identified in the PI3K/AKT or RAS/RAF pathways. The p53 immunohistochemical examination revealed a wild-type expression pattern in cases 1-3 and strong expression in case 4. The results of p16 immunostaining were negative in all cases. CONCLUSIONS We described four previously unreported genetic characteristics of dorsal tongue SCC. Somatic TP53 mutations may contribute to the development of a subset of dorsal tongue SCC; however, more cases with genetic analysis need to be accumulated.
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Affiliation(s)
- Sawako Ono
- Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, 700-8558, Japan
| | - Katsutoshi Hirose
- Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Shintaro Sukegawa
- Department of Oral and Maxillofacial Surgery, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Kyoichi Obata
- Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, 700-8558, Japan
| | - Masanori Masui
- Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, 1-2-1 Asahimachi, Takamatsu, Kagawa, 760-8557, Japan
| | - Kazuaki Hasegawa
- Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, 1-2-1 Asahimachi, Takamatsu, Kagawa, 760-8557, Japan
| | - Ai Fujimura
- Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, 1-2-1 Asahimachi, Takamatsu, Kagawa, 760-8557, Japan
| | - Katsumitsu Shimada
- Department of Clinical Pathophysiology, Matsumoto Dental University Graduate School of Oral Medicine, 1780 Gobara Hirooka, Shiojiri, Nagano, 399-0781, Japan
| | - Satoko Nakamura
- Department of Pathology, Kagawa Prefectural Central Hospital, 1-2-1 Asahimachi, Takamatsu, Kagawa, 760-8557, Japan
| | - Akari Teramoto
- Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yumiko Hori
- Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Central Laboratory and Surgical Pathology, NHO Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka, Osaka, 540-0006, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Daisuke Motooka
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takuro Igawa
- Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, 700-8558, Japan
| | - Takehiro Tanaka
- Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, 700-8558, Japan
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, 700-8558, Japan
| | - Satoru Toyosawa
- Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidetaka Yamamoto
- Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, 700-8558, Japan
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Kato M, Ota A, Ono T, Karnan S, Hyodo T, Rahman ML, Hasan MN, Onda M, Kondo S, Ito K, Furuhashi A, Hayashi T, Konishi H, Tsuzuki S, Hosokawa Y, Kazaoka Y. PDZ-binding kinase inhibitor OTS514 suppresses the proliferation of oral squamous carcinoma cells. Oral Dis 2024; 30:223-234. [PMID: 36799330 DOI: 10.1111/odi.14533] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 12/28/2022] [Accepted: 02/09/2023] [Indexed: 02/18/2023]
Abstract
OBJECTIVE PDZ-binding kinase (PBK) has been reported as a poor prognostic factor and is a promising molecular target for anticancer therapeutics. Here, we aimed to investigate the effect of specific PBK inhibitor OTS514 on the survival of OSCC cells. METHODS Four OSCC cell lines (HSC-2, HSC-3, SAS, and OSC-19) were used to examine the effect of OTS514 on cell survival and apoptosis. DNA microarray analysis was conducted to investigate the effect of OTS514 on gene expression in OSCC cells. Gene set enrichment analysis was performed to identify molecular signatures related to the antiproliferative effect of OTS514. RESULTS OTS514 decreased the cell survival of OSCC cells dose-dependently, and administration of OTS514 readily suppressed the HSC-2-derived tumor growth in immunodeficient mice. Treatment with OTS514 significantly increased the number of apoptotic cells and caspase-3/7 activity. Importantly, OTS514 suppressed the expression of E2F target genes with a marked decrease in protein levels of E2F1, a transcriptional factor. Moreover, TP53 knockdown attenuated OTS514-induced apoptosis. CONCLUSION OTS514 suppressed the proliferation of OSCC cells by downregulating the expression of E2F target genes and induced apoptosis by mediating the p53 signaling pathway. These results highlight the clinical application of PBK inhibitors in the development of molecular-targeted therapeutics against OSCC.
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Affiliation(s)
- Mikako Kato
- Department of Oral and Maxillofacial Surgery, Aichi Medical University Hospital, Nagakute, Japan
| | - Akinobu Ota
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Takayuki Ono
- Department of Oral and Maxillofacial Surgery, Aichi Medical University Hospital, Nagakute, Japan
| | - Sivasundaram Karnan
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Toshinori Hyodo
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Md Lutfur Rahman
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Muhammad Nazmul Hasan
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Maho Onda
- Department of Oral and Maxillofacial Surgery, Aichi Medical University Hospital, Nagakute, Japan
| | - Sayuri Kondo
- Department of Oral and Maxillofacial Surgery, Aichi Medical University Hospital, Nagakute, Japan
| | - Kunihiro Ito
- Department of Oral and Maxillofacial Surgery, Aichi Medical University Hospital, Nagakute, Japan
| | - Akifumi Furuhashi
- Department of Oral and Maxillofacial Surgery, Aichi Medical University Hospital, Nagakute, Japan
| | - Tomio Hayashi
- Department of Oral and Maxillofacial Surgery, Aichi Medical University Hospital, Nagakute, Japan
| | - Hiroyuki Konishi
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Shinobu Tsuzuki
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshitaka Hosokawa
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshiaki Kazaoka
- Department of Oral and Maxillofacial Surgery, Aichi Medical University Hospital, Nagakute, Japan
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7
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Hirose K, Shibahara T, Teramoto A, Usami Y, Ono S, Iwamoto Y, Murakami S, Oya K, Uzawa N, Motooka D, Hori Y, Morii E, Toyosawa S. Clear Cell Squamous Cell Carcinoma of the Maxillary Gingiva Associated with PIK3CA and HRAS Mutations: Report of a Case and Literature Review. Head Neck Pathol 2023; 17:1026-1033. [PMID: 37735286 PMCID: PMC10739645 DOI: 10.1007/s12105-023-01580-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/11/2023] [Indexed: 09/23/2023]
Abstract
BACKGROUND Squamous cell carcinoma (SCC) is the most common oral malignancy, and somatic mutations in some driver genes have been implicated in SCC development. Clear cell SCC (CCSCC) is a rare histological variant of SCC, and various clear cell neoplasms must be considered in the differential diagnosis of CCSCC in the oral cavity. Based on a limited number of CCSCC cases reported in the oral cavity, CCSCC is considered an aggressive variant of SCC with a poor prognosis; however, its genetic characteristics remain unknown. METHODS A maxillary gingival tumor in an 89-year-old female was described and investigated using immunohistochemical staining, special staining, fluorescence in situ hybridization, and next-generation sequencing (NGS) with a custom panel of driver genes, including those associated with SCC and clear cell neoplasm development. RESULTS Histopathological examination revealed a proliferation of atypical epithelial cells with abundant clear cytoplasm and enlarged and centrally placed round nuclei. The tumor was exophytic with deep, penetrating proliferation. The atypical clear cells were continuous with the conventional SCC cells. Immunohistochemical analysis showed that the clear cells were positive for CK AE1/AE3 and CK5/6 and nuclear-positive for p63. In contrast, the clear cells were negative for αSMA, S100, HMB45, Melan-A, CD10, and p16. p53 immunoreactivity exhibited a wild-type expression pattern. Additionally, the clear cells were positive for periodic acid-Schiff (PAS) and negative for diastase-PAS, mucicarmine, and Alcian blue. Based on these results, the diagnosis of CCSCC was confirmed. Molecular analysis of the clear cells identified PIK3CA p.E542K (c.1624G>A) and HRAS p.G12A (c.35 G>C) somatic mutations classified as oncogenic. No pathogenic variants were identified in TP53, EWSR1, AKT1, PTEN, BRAF, KRAS, NRAS, RASA1, or MAML2. CONCLUSIONS We report a case of CCSCC of the oral cavity with PIK3CA and HRAS mutations. The identification of PIK3CA and/or HRAS mutations is rare in SCC; however, both mutations are important potential targets for antitumor therapy. A detailed analysis of gene mutations in CCSCC may lead to a better understanding of its biological behavior and an improved prognosis, as well as a differential diagnosis from other clear cell neoplasms.
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Affiliation(s)
- Katsutoshi Hirose
- Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Takumi Shibahara
- Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Oral & Maxillofacial Oncology and Surgery, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Akari Teramoto
- Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Oral & Maxillofacial Oncology and Surgery, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yu Usami
- Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Sawako Ono
- Department of Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8558, Japan
| | - Yuri Iwamoto
- Department of Oral and Maxillofacial Radiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shumei Murakami
- Department of Oral and Maxillofacial Radiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kaori Oya
- Clinical Laboratory, Osaka University Dental Hospital, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Narikazu Uzawa
- Department of Oral & Maxillofacial Oncology and Surgery, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Daisuke Motooka
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yumiko Hori
- Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Central Laboratory and Surgical Pathology, National Hospital Organization, Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Satoru Toyosawa
- Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
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8
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Jagadeeshan S, Novoplansky OZ, Cohen O, Kurth I, Hess J, Rosenberg AJ, Grandis JR, Elkabets M. New insights into RAS in head and neck cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188963. [PMID: 37619805 PMCID: PMC11815531 DOI: 10.1016/j.bbcan.2023.188963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/15/2023] [Accepted: 08/15/2023] [Indexed: 08/26/2023]
Abstract
RAS genes are known to be dysregulated in cancer for several decades, and substantial effort has been dedicated to develop agents that reduce RAS expression or block RAS activation. The recent introduction of RAS inhibitors for cancer patients highlights the importance of comprehending RAS alterations in head and neck cancer (HNC). In this regard, we examine the published findings on RAS alterations and pathway activations in HNC, and summarize their role in HNC initiation, progression, and metastasis. Specifically, we focus on the intrinsic role of mutated-RAS on tumor cell signaling and its extrinsic role in determining tumor-microenvironment (TME) heterogeneity, including promoting angiogenesis and enhancing immune escape. Lastly, we summarize the intrinsic and extrinsic role of RAS alterations on therapy resistance to outline the potential of targeting RAS using a single agent or in combination with other therapeutic agents for HNC patients with RAS-activated tumors.
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Affiliation(s)
- Sankar Jagadeeshan
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel.
| | - Ofra Z Novoplansky
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel.
| | - Oded Cohen
- Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel; Department of Otolaryngology- Head and Neck Surgery and Oncology, Soroka Medical Center, Beersheva, Israel.
| | - Ina Kurth
- Division of Radiooncology-Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Jochen Hess
- Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany; Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
| | - Ari J Rosenberg
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA.
| | - Jennifer R Grandis
- Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, CA, USA.
| | - Moshe Elkabets
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 8410501, Israel.
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9
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Chiesa-Estomba CM, Thompson L, Agaimy A, Zidar N, Simpson RHW, Franchi A, Rodrigo JP, Mäkitie AA, Almangush A, Leivo I, Ferlito A. Predictive value of tumor budding in head and neck squamous cell carcinoma: an update. Virchows Arch 2023; 483:441-449. [PMID: 37642731 DOI: 10.1007/s00428-023-03630-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/16/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023]
Abstract
Head and neck squamous cell carcinoma forms an anatomically and functionally complex group of malignancies. The significant local aggressiveness and frequent regional relapses motivate ongoing research to identify more reliable and sensitive prognostic and predictive biomarkers. One emerging area of cancer biology is the evaluation of tumor budding at the advancing invasive front of various types of epithelial cancers. Recent studies suggest that tumor budding is a relatively common phenomenon in cancer progression and that it may have important prognostic implications for patients due to its potential to provide valuable insights into the biology and clinical behavior of head and neck cancer. In this review, we aim to provide information about tumor budding in head and neck squamous cell carcinoma. Thus, we hope to shed light on the complex biology of these malignancies, as well as aiding diagnostic, classification, and better characterization and thereby, looking for new avenues for improving patient outcomes.
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Affiliation(s)
- Carlos M Chiesa-Estomba
- Department of Otorhinolaryngology, Osakidetza, Donostia University Hospital, Biodonostia Research Institute, 20014, San Sebastian, Spain.
- Otorhinolaryngology Department, Faculty of Medicine, Deusto University, Bilbao, Spain.
| | - Lester Thompson
- Head and Neck Pathology Consultations, Woodland Hills, CA, 91364, USA
| | - Abbas Agaimy
- Institut Für Pathologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000, Ljubljana, Slovenia
| | | | - Alessandro Franchi
- Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, 56126, Pisa, Italy
| | - Juan P Rodrigo
- Department of Otolaryngology, Hospital Universitario Central de Asturias, University of Oviedo, ISPA, IUOPA, CIBERONC, Oviedo, Spain
| | - Antti A Mäkitie
- Department of Otorhinolaryngology-Head and Neck Surgery, Research Program in Systems Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Alhadi Almangush
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Ilmo Leivo
- Institute of Biomedicine, Pathology, University of Turku, Turku, Finland
| | - Alfio Ferlito
- Coordinator of the International Head and Neck, Scientific Group, Padua, Italy
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10
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Mohammedsaleh ZM, Moawadh MS, Saleh FM, Jalal MM, Al-Otaibi AS, Saeedi NH, Baskaran R, Huang CY, Kumar VB. Increased NOTCH1 expression is associated with low survival in moderate/ poor differentiated human oral squamous cell carcinoma patients. J Cancer 2023; 14:3023-3027. [PMID: 37859809 PMCID: PMC10583578 DOI: 10.7150/jca.87128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 09/09/2023] [Indexed: 10/21/2023] Open
Abstract
Notch deregulation has been reported in various types of cancers, including Oral squamous cell carcinomas (OSCCs). The role of Notch1 signaling in oral squamous cell carcinoma (OSCC) remains poorly understood. In this study, NOTCH1 was aberrantly expressed in human oral cancer tissues compared with that in normal marginal tissues and was associated with poor prognosis. The positive Notch 1 expression was significantly associated with poor tumor differentiation status. Kaplan-Meier survival curves revealed that elevated cytoplasmic NOTCH1 expression levels in OSCC patients were associated with poor overall survival. Moreover, multivariate COX proportional hazard models revealed that T N status, AJCC stage histological grade were independent prognostic factors for survival. Our result clearly demonstrates the oncogenic role of Notch1 in oral cancer and Notch1 may be a useful biomarker to target oral cancer patients.
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Affiliation(s)
- Zuhair M. Mohammedsaleh
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Mamdoh S. Moawadh
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Fayez M. Saleh
- Department of Medical Microbiology, Faculty of Medicine, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Mohammed M. Jalal
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Abdulaziz S Al-Otaibi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Nizar H. Saeedi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Rathinasamy Baskaran
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
| | - Chih-Yang Huang
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan
| | - V. Bharath Kumar
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413, Taiwan
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11
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Okuyama K, Suzuki K, Yanamoto S. Relationship between Tumor Budding and Partial Epithelial-Mesenchymal Transition in Head and Neck Cancer. Cancers (Basel) 2023; 15:cancers15041111. [PMID: 36831453 PMCID: PMC9953904 DOI: 10.3390/cancers15041111] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/04/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Tumor budding (TB), a microscopic finding in the stroma ahead of the invasive fronts of tumors, has been well investigated and reported as a prognostic marker in head and neck squamous cell carcinoma (HNSCC). Epithelial-mesenchymal transition (EMT) is a crucial step in tumor progression and metastasis, and its status cannot be distinguished from TB. The current understanding of partial EMT (p-EMT), the so-called halfway step of EMT, focuses on the tumor microenvironment (TME). Although this evidence has been investigated, the clinicopathological and biological relationship between TB and p-EMT remains debatable. At the invasion front, previous research suggested that cancer-associated fibroblasts (CAFs) are important for tumor progression, metastasis, p-EMT, and TB formation in the TME. Although there is biological evidence of TB drivers, no report has focused on their organized functional relationships. Understanding the mechanism of TB onset and the relationship between p-EMTs may facilitate the development of novel diagnostic and prognostic methods, and targeted therapies for the prevention of metastasis in epithelial cancer. Thus far, major pieces of evidence have been established from colorectal cancer (CRC), due to a large number of patients with the disease. Herein, we review the current understanding of p-EMT and TME dynamics and discuss the relationship between TB development and p-EMT, focusing on CAFs, hypoxia, tumor-associated macrophages, laminin-integrin crosstalk, membrane stiffness, enzymes, and viral infections in cancers, and clarify the gap of evidence between HNSCC and CRC.
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Affiliation(s)
- Kohei Okuyama
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, 1011 North University Ave, Ann Arbor, MI 48109, USA
- University of Michigan Rogel Cancer Center, 1600 Huron Pathway, Ann Arbor, MI 48105, USA
- Department of Oral and Maxillofacial Surgical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Correspondence: or
| | - Keiji Suzuki
- Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan
| | - Souichi Yanamoto
- Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan
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12
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Dholariya S, Singh RD, Sonagra A, Yadav D, Vajaria BN, Parchwani D. Integrating Cutting-Edge Methods to Oral Cancer Screening, Analysis, and Prognosis. Crit Rev Oncog 2023; 28:11-44. [PMID: 37830214 DOI: 10.1615/critrevoncog.2023047772] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2023]
Abstract
Oral cancer (OC) has become a significant barrier to health worldwide due to its high morbidity and mortality rates. OC is among the most prevalent types of cancer that affect the head and neck region, and the overall survival rate at 5 years is still around 50%. Moreover, it is a multifactorial malignancy instigated by genetic and epigenetic variabilities, and molecular heterogeneity makes it a complex malignancy. Oral potentially malignant disorders (OPMDs) are often the first warning signs of OC, although it is challenging to predict which cases will develop into malignancies. Visual oral examination and histological examination are still the standard initial steps in diagnosing oral lesions; however, these approaches have limitations that might lead to late diagnosis of OC or missed diagnosis of OPMDs in high-risk individuals. The objective of this review is to present a comprehensive overview of the currently used novel techniques viz., liquid biopsy, next-generation sequencing (NGS), microarray, nanotechnology, lab-on-a-chip (LOC) or microfluidics, and artificial intelligence (AI) for the clinical diagnostics and management of this malignancy. The potential of these novel techniques in expanding OC diagnostics and clinical management is also reviewed.
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Affiliation(s)
- Sagar Dholariya
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Rajkot, Gujarat, India
| | - Ragini D Singh
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Rajkot, Gujarat, India
| | - Amit Sonagra
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Rajkot, Gujarat, India
| | | | | | - Deepak Parchwani
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Rajkot, Gujarat, India
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13
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Chuang HC, Tsai MH, Lin YT, Chou MH, Yang KL, Chien CY. Systemic and Local Effects Among Patients With Betel Quid-Related Oral Cancer. Technol Cancer Res Treat 2022; 21:15330338221146870. [PMID: 36575633 PMCID: PMC9806389 DOI: 10.1177/15330338221146870] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The major predisposing factors of developing oral cancer include smoking, alcohol drinking, and betel quid chewing. Betel quid chewing could cause the abrasion and damage of oral mucosa by crude fibers, chemical insults by additive slaked lime, and arecoline from areca nut. These would lead to the local consequence of oral submucosal fibrosis, which is regarded clinically as a precancer lesion and a major cause of trismus. In addition, the components and additives in betel quid contain chemical toxins and carcinogens, which would further affect the oral mucosa and gradually develop a malignancy. Following literature review, aside from having a greater total tumor burden and more local diseases in the oral cavity and digestive tract, patients with betel quid-related oral cancer also have more systemic diseases from metabolic syndrome, hypertension, cardiovascular disease, type II diabetes mellitus, and obesity than those without this habit. In conclusion, those patients who have the history of smoking, alcohol drinking, and betel quid chewing would present much more unique clinical characteristics than those who only have a history of smoking and alcohol drinking. More attention should therefore be paid to pretreatment evaluation, treatment strategy, and posttreatment follow-up among betel quid chewers.
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Affiliation(s)
- Hui-Ching Chuang
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan,Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung , Taiwan,Center for mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ming-Hsien Tsai
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan,Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung , Taiwan
| | - Yu-Tsai Lin
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan,Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung , Taiwan
| | - Ming-Huei Chou
- Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung , Taiwan,Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan,Center for General Education, Cheng-Shiu University, Kaohsiung, Taiwan
| | - Kun-Lin Yang
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan,Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung , Taiwan
| | - Chih-Yen Chien
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan,Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung , Taiwan,Chang Gung Molecular Medicine Research Center, Taiwan ,Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Taiwan,Chih-Yen Chien, Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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14
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Shen T, Yang T, Yao M, Zheng Z, He M, Shao M, Li J, Fang C. BTC as a Novel Biomarker Contributing to EMT via the PI3K-AKT Pathway in OSCC. Front Genet 2022; 13:875617. [PMID: 35846125 PMCID: PMC9283838 DOI: 10.3389/fgene.2022.875617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Purpose: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of the head and neck, while metastasis is the main cause of OSCC-related death. There is an urgent need to explore novel prognostic biomarkers and identify biological targets related to metastasis in OSCC treatment.Methods: Analysis of differential expression was performed using datasets in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Immunohistochemistry (IHC) was conducted to assess the expression of betacellulin (BTC) in OSCC. SCC4 and CAL27 cells were used for in vitro experiments, in which CCK-8, transwell assays, and wounding healing assays were performed to verify the biological functions of BTC. The role of BTC in EMT was analyzed by EMT score and Western blot.Results: Through the analysis of the mRNA expression profile data from TCGA database in OSCC, we found that only low expression of BTC was significantly correlated with a poor prognosis in OSCC patients. The results of IHC assays and TCGA databases showed that the expression level of BTC was related to the tumor stage, histological grade, and metastasis status. In vitro analysis showed that overexpression of BTC significantly suppressed the proliferation and migration of OSCC cells. Furthermore, we confirmed that BTC could affect EMT through the PI3K-AKT signaling pathway.Conclusion: The overexpression of BTC suppresses the proliferation, migration, and EMT of OSCC cells via the PI3K-AKT pathways, leading to a better prognosis in OSCC. BTC may be used as a novel molecular marker to assess the prognosis of OSCC patients.
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Affiliation(s)
- Ting Shen
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Tianru Yang
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Mianfeng Yao
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Ziran Zheng
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Mi He
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Mengying Shao
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Jiang Li
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
- *Correspondence: Jiang Li, ; Changyun Fang,
| | - Changyun Fang
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
- *Correspondence: Jiang Li, ; Changyun Fang,
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15
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Abstract
ABSTRACT Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most prevalent cancer worldwide, with an annual incidence of 600,000 new cases. Despite advances in surgery, chemotherapy, and radiotherapy, the overall survival for HNSCC patients has not been significantly improved over the past several decades. Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) genomic alterations are frequently detected in HNSCC, including amplification, activating mutation, and chromosomal rearrangement. Among them, FGFR1 amplification, FGF amplifications, and FGFR3 mutations are the most prevalent. In addition, FGF/FGFR expression has also been observed in most HNSCCs. However, the prognostic value of FGF/FGFR aberrations remains unclear, especially for gene amplification and overexpression. Nonetheless, FGF/FGFR has been a promising target for HNSCC treatment, and recent preclinical studies demonstrate the potential of the combination treatment regimens involving FGFR inhibitors on HNSCC. Therefore, there are a number of FGFR inhibitors currently in clinical trials for the treatment of head and neck cancers.
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16
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Liao CT, Yang LY, Lee LY, Lin CY, Wang HM, Ng SH, Yen TC, Fan WL, Hsieh JCH. Whole-exome sequencing identifies biosignatures that predict adverse survival outcomes in surgically treated patients with oral cavity squamous cell carcinoma. Oral Oncol 2021; 122:105547. [PMID: 34700279 DOI: 10.1016/j.oraloncology.2021.105547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 09/10/2021] [Accepted: 09/21/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVES The postoperative outcomes of patients with oral cavity squamous cell carcinoma (OCSCC) vary greatly. To improve risk stratification, we sought to identify genetic biosignatures by whole-exome sequencing (WES). MATERIALS AND METHODS We retrieved patients with OCSCC patients with paired freshly frozen malignant and non-malignant tissue specimens and performed WES by Illumina HiSeq4000 platform. We further applied a tree-based method to analyze copy number variations and obtain signature classification and driver-gene identification. We further confirmed the prognostic impact of the WES biosignature in an external independent validation set. RESULTS We examined 168 paired samples from patients with surgically treated OCSCC. Similar to the literature, the most commonly mutated genes were TP53 (66%), FAT1 (32%), and NOTCH1 (24%). The signatures 13 (APOBEC Cytidine deaminase [C > G]), 1 (spontaneous deamination of 5-methylcytosine), and 7 (UV exposure) showed the highest concordance rates. Using the MutSigCV, MuSiC, 20/20+, OncodriveFML, e-Driver, OncodriveCLUST, and tree-based methods, we identified a nine-gene OCSCC panel (RYR1, HLA-B, TSHZ2, PCDH17, DNAH17, GRID1, SBNO2, KSR2, and GCN1L1) predicting survival outcomes in our sample. We used the TCGA database to validate the prognostic value of the panel independently. Furthermore, gene-gene covariance analysis confirmed the coexistence of several gene alterations. CONCLUSION We identified and independently validated a WES biosignature that predicts outcomes in surgically treated OCSCC in Taiwan, a betel-quid-chewing-prevent area. We proposed that the panel might help clinical trial designation for adjuvant therapy based on the risk stratification from the novel gene panel and identify targets for liquid biopsy monitoring during surveillance.
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Affiliation(s)
- Chun-Ta Liao
- Departments of Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Chang Gung University, College of Medicine, Taoyuan 333, Taiwan
| | - Lan-Yan Yang
- Department of Biostatistics and Informatics Unit, Clinical Trial Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Chang Gung University, College of Medicine, Taoyuan 333, Taiwan
| | - Li-Yu Lee
- Department of Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Chang Gung University, College of Medicine, Taoyuan 333, Taiwan
| | - Chien-Yu Lin
- Department of Radiation Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Chang Gung University, College of Medicine, Taoyuan 333, Taiwan
| | - Hung-Ming Wang
- Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Chang Gung University, College of Medicine, Taoyuan 333, Taiwan
| | - Shu-Hang Ng
- Department of Diagnostic Radiology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Chang Gung University, College of Medicine, Taoyuan 333, Taiwan
| | - Tzu-Chen Yen
- Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Chang Gung University, College of Medicine, Taoyuan 333, Taiwan
| | - Wen-Lang Fan
- Department of Biostatistics and Informatics Unit, Clinical Trial Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Chang Gung University, College of Medicine, Taoyuan 333, Taiwan.
| | - Jason Chia-Hsun Hsieh
- Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; New Taipei Municipal TuCheng Hospital, New Taipei City 236, Taiwan; Chang Gung University, College of Medicine, Taoyuan 333, Taiwan.
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Fan WL, Yang LY, Hsieh JCH, Lin TC, Lu MYJ, Liao CT. Prognostic Genetic Biomarkers Based on Oncogenic Signaling Pathways for Outcome Prediction in Patients with Oral Cavity Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13112709. [PMID: 34070941 PMCID: PMC8199274 DOI: 10.3390/cancers13112709] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 01/02/2023] Open
Abstract
Simple Summary A comprehensive analysis based on mutational signatures and oncogenic signaling pathways to identify a specific subgroup of patients that had a significantly negative impact on both disease-free and overall survival in oral cavity squamous cell carcinoma (OCSCC) from whole exome-sequencing data. This analysis has revealed a variety of biologically relevant candidate target genes. Thirty percent of 165 tumors had multiple targetable alterations in multiple pathways. This suggests the complex interplay and crosstalk of oncogenic signaling pathways play an important role on the outcome of patients with OCSCC, and the candidate genes and pathways identified may include prognostic genetic biomarkers or therapeutic targets for OCSCC. Abstract Mutational profiling of patients’ tumors has suggested that the development of oral cavity squamous cell carcinoma (OCSCC) is driven by multiple genes in multiple pathways. This study aimed to examine the association between genomic alterations and clinical outcomes in patients with advanced stages OCSCC to facilitate prognostic stratification. We re-analyzed our previous whole-exome sequencing data from 165 long-term follow-ups of stages III and IV patients with OCSCC. Their frequent mutations were mapped to 10 oncogenic signaling pathways. Clinicopathological risk factors, relapse, and survival were analyzed to identify the genetic factors associated with advanced OCSCC. Frequent genetic alterations included point mutations in TP53, FAT1, NOTCH1, CASP8, CDKN2A, HRAS, PIK3CA, KMT2B (also known as MLL4), and LINC00273; amplified segments in CCND1, EGFR, CTTN, and FGFR1; and lost segments in CDKN2A, ADAM3A, and CFHR1/CFHR4. Comprehensive analysis of genetic alterations revealed that subgroups based on mutational signatures had a significant negative impact on disease-free survival (p = 0.0005) and overall survival (p = 0.0024). Several important signaling pathways were identified to be frequently genetically altered in our cohort. A specific subgroup of patients with alterations in NOTCH, RTK/RAS/MAPK, and TGF-beta pathways that had a significantly negative impact on disease-free survival (p = 0.0009). Thirty percent of samples had multiple targetable mutations in multiple pathways, indicating opportunities for novel therapy.
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Affiliation(s)
- Wen-Lang Fan
- Genomic Medicine Core Laboratory, Linkou Chang Gung Memorial Hospital, Taoyuan 33382, Taiwan; (W.-L.F.); (T.-C.L.)
| | - Lan-Yan Yang
- Clinical Trial Center, Biostatistics and Informatics Unit, Linkou Chang Gung Memorial Hospital, Taoyuan 33382, Taiwan;
| | - Jason Chia-Hsun Hsieh
- Department of Internal Medicine, Division of Hematology-Oncology, New Taipei Municipal TuCheng Hospital, New Taipei City 236043, Taiwan;
- Medical Oncology, Linkou Chang Gung Memorial Hospital, Taoyuan 33382, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan
| | - Tsung-Chieh Lin
- Genomic Medicine Core Laboratory, Linkou Chang Gung Memorial Hospital, Taoyuan 33382, Taiwan; (W.-L.F.); (T.-C.L.)
| | - Mei-Yeh Jade Lu
- Biodiversity Research Center, Academia Sinica, Taipei 11529, Taiwan;
| | - Chun-Ta Liao
- Department of Otorhinolaryngology, Head and Neck Surgery, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 33382, Taiwan
- Correspondence:
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Moura ACD, Assad DX, Amorim Dos Santos J, Porto de Toledo I, Barra GB, Castilho RM, Squarize CH, Guerra ENS. Worldwide prevalence of PI3K-AKT-mTOR pathway mutations in head and neck cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2021; 160:103284. [PMID: 33675910 DOI: 10.1016/j.critrevonc.2021.103284] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 02/03/2021] [Accepted: 02/27/2021] [Indexed: 02/07/2023] Open
Abstract
A systematic review (SR) and meta-analysis were conducted to determine the prevalence of PI3K-AKT-mTOR signaling pathway mutations in patients with head and neck cancer (HNC). Overall, 105 studies comprising 8630 patients and 1306 mutations were selected. The estimated mutations prevalence was 13 % for PIK3CA (95 % confidence interval [CI] = 11-14; I2 = 82 %; p < 0.0001), 4% for PTEN (95 % CI = 3-5; I2 = 55 %; p < 0.0001), 3% for MTOR (95 % CI = 2-4; I2 = 5%; p = 0.40), and 2% for AKT (95 % CI = 1-2; I2 = 50 %; p = 0.0001). We further stratified the available data of the participants according to risk factors and tumor characteristics, including HPV infection, tobacco use, alcohol exposure, TNM stage, and histological tumor differentiation, and performed subgroup analysis. We identified significant associations between PI3K-AKT-mTOR pathway-associated mutations and advanced TNM stage (odds ratio [OR] = 0.20; 95 % CI = 0.09-0.44; I² = 71 %; p = 0.0001) and oropharyngeal HPV-positive tumors and PIK3CA mutations (OR = 17.48; 95 % CI = 4.20-72.76; I² = 69 %; p < 0.0002). No associations were found between alcohol and tobacco exposure, and tumor differentiation grade. This SR demonstrated that the PI3K-AKT-mTOR pathway emerges as a potential prognostic factor and could offer a molecular basis for future studies on therapeutic targeting in HNC patients.
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Affiliation(s)
- Adriana Castelo de Moura
- Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília, Brasília, Brazil; Hospital Universitário de Brasília (HUB-UnB/Ebserh), Brasília, DF, Brazil; Hospital Santa Lúcia, Brasília, DF, Brazil
| | - Daniele Xavier Assad
- Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília, Brasília, Brazil; Medical Oncology Department, Hospital Sírio-Libanês, Brasília, DF, Brazil
| | - Juliana Amorim Dos Santos
- Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília, Brasília, Brazil
| | - Isabela Porto de Toledo
- Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília, Brasília, Brazil
| | - Gustavo Barcelos Barra
- Sabin Medicina Diagnóstica, SAAN Quadra 03 Lotes 145/185, Brasília, 70632-340, DF, Brazil
| | - Rogerio Moraes Castilho
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, Division of Oral Pathology, Radiology and Medicine, University of Michigan School of Dentistry. Ann Arbor, 48109-1078, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Cristiane Helena Squarize
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, Division of Oral Pathology, Radiology and Medicine, University of Michigan School of Dentistry. Ann Arbor, 48109-1078, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Eliete Neves Silva Guerra
- Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília, Brasília, Brazil; Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, Division of Oral Pathology, Radiology and Medicine, University of Michigan School of Dentistry. Ann Arbor, 48109-1078, MI, USA.
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Koo K, Mouradov D, Angel CM, Iseli TA, Wiesenfeld D, McCullough MJ, Burgess AW, Sieber OM. Genomic Signature of Oral Squamous Cell Carcinomas from Non-Smoking Non-Drinking Patients. Cancers (Basel) 2021; 13:cancers13051029. [PMID: 33804510 PMCID: PMC7957667 DOI: 10.3390/cancers13051029] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/15/2021] [Accepted: 02/22/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary A clinically distinct cohort of non-smoking non-drinking patients who develop oral cavity squamous cell carcinomas has been identified, with previous work suggesting that these patients tend to be older, female, and have poor outcomes. Our study characterised tumour molecular alterations in these patients, identifying differences in genomic profiles as compared to patients who smoke and/or drink. Associations between molecular alterations and other clinical and pathological characteristics were also explored. Abstract Molecular alterations in 176 patients with oral squamous cell carcinomas (OSCC) were evaluated to delineate differences in non-smoking non-drinking (NSND) patients. Somatic mutations and DNA copy number variations (CNVs) in a 68-gene panel and human papilloma virus (HPV) status were interrogated using targeted next-generation sequencing. In the entire cohort, TP53 (60%) and CDKN2A (24%) were most frequently mutated, and the most common CNVs were EGFR amplifications (9%) and deletions of BRCA2 (5%) and CDKN2A (4%). Significant associations were found for TP53 mutation and nodal disease, lymphovascular invasion and extracapsular spread, CDKN2A mutation or deletion with advanced tumour stage, and EGFR amplification with perineural invasion and extracapsular spread. PIK3CA mutation, CDKN2A deletion, and EGFR amplification were associated with worse survival in univariate analyses (p < 0.05 for all comparisons). There were 59 NSND patients who tended to be female and older than patients who smoke and/or drink, and showed enrichment of CDKN2A mutations, EGFR amplifications, and BRCA2 deletions (p < 0.05 for all comparisons), with a younger subset showing higher mutation burden. HPV was detected in three OSCC patients and not associated with smoking and drinking habits. NSND OSCC exhibits distinct genomic profiles and further exploration to elucidate the molecular aetiology in these patients is warranted.
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Affiliation(s)
- Kendrick Koo
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC 3052, Australia; (K.K.); (D.M.); (A.W.B.)
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3050, Australia; (T.A.I.); (D.W.)
- Melbourne Dental School, The University of Melbourne, Carlton, VIC 3053, Australia;
| | - Dmitri Mouradov
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC 3052, Australia; (K.K.); (D.M.); (A.W.B.)
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
| | | | - Tim A. Iseli
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3050, Australia; (T.A.I.); (D.W.)
| | - David Wiesenfeld
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3050, Australia; (T.A.I.); (D.W.)
- Melbourne Dental School, The University of Melbourne, Carlton, VIC 3053, Australia;
| | | | - Antony W. Burgess
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC 3052, Australia; (K.K.); (D.M.); (A.W.B.)
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3050, Australia; (T.A.I.); (D.W.)
| | - Oliver M. Sieber
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC 3052, Australia; (K.K.); (D.M.); (A.W.B.)
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3050, Australia; (T.A.I.); (D.W.)
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
- Correspondence:
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20
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Uchibori M, Osawa Y, Ishii Y, Aoki T, Ota Y, Kimura M. Analysis of HRAS mutations in Japanese patients with oral squamous cell carcinoma. ADVANCES IN ORAL AND MAXILLOFACIAL SURGERY 2021. [DOI: 10.1016/j.adoms.2021.100021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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21
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Johnston KM, Sheffield BS, Yip S, Lakzadeh P, Qian C, Nam J. Comprehensive genomic profiling for non-small-cell lung cancer: health and budget impact. Curr Oncol 2020; 27:e569-e577. [PMID: 33380872 PMCID: PMC7755443 DOI: 10.3747/co.27.5995] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background Single-gene tests and hotspot panels targeting specific subsets of biomarkers constitute the Canadian genomic testing landscape for non-small-cell lung cancer (nsclc). However, newer testing options such as comprehensive genomic profiling (cgp) offer improved detection rates and identification of multiple classes of genomic alterations in a single assay, minimizing tissue requirements and turnaround time. The objective of the present analysis was to assess the health and budget impacts of adopting cgp testing for nsclc in Canada. Methods This study assessed the impact of funding the cgp tests FoundationOne CDx and FoundationOne Liquid (Foundation Medicine, Cambridge, MA, U.S.A.) over a 3-year time horizon using a Canadian societal perspective for Ontario. Conventional testing strategies were summarized into two reference scenarios: a series of single-gene tests only, and reflex single-gene testing followed by a hotspot panel for negative results. Four adoption scenarios for cgp testing were considered: replacing all single-gene and hotspot panel testing, replacing hotspot panel testing only, use after negative single-gene and hotspot testing, and use of FoundationOne Liquid in individuals with insufficient tissue for conventional testing. Results When cgp testing was assumed to replace all conventional testing with 50% uptake, the budget impact per person per year ranged from $0.71 to $0.87, depending on the reference scenario, with a 3-year gain of 680.9 life-years and 3831 working days over the full cohort. Conclusions Given the present testing landscape for patients with nsclc in Canada, listing cgp testing could optimize the selection of appropriately targeted treatments, and thus add life-years and productivity for this population, with a minimal budget impact.
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Affiliation(s)
- K M Johnston
- Broadstreet Health Economics and Outcomes Research, Vancouver, BC
| | | | - S Yip
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC
| | - P Lakzadeh
- Broadstreet Health Economics and Outcomes Research, Vancouver, BC
| | - C Qian
- Broadstreet Health Economics and Outcomes Research, Vancouver, BC
| | - J Nam
- Market Access and Pricing, Hoffmann-La Roche Ltd., Mississauga, ON
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Kim S, Lee JW, Park YS. The Application of Next-Generation Sequencing to Define Factors Related to Oral Cancer and Discover Novel Biomarkers. Life (Basel) 2020; 10:E228. [PMID: 33023080 PMCID: PMC7599837 DOI: 10.3390/life10100228] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 02/07/2023] Open
Abstract
Despite the introduction of next-generation sequencing in the realm of DNA sequencing technology, it is not often used in the investigation of oral squamous cell carcinoma (OSCC). Oral cancer is one of the most frequently occurring malignancies in some parts of the world and has a high mortality rate. Patients with this malignancy are likely to have a poor prognosis and may suffer from severe facial deformity or mastication problems even after successful treatment. Therefore, a thorough understanding of this malignancy is essential to prevent and treat it. This review sought to highlight the contributions of next-generation sequencing (NGS) in unveiling the genetic alterations and differential expressions of miRNAs involved in OSCC progression. By applying an appropriate eligibility criterion, we selected relevant studies for review. Frequently identified mutations in genes such as TP53, NOTCH1, and PIK3CA are discussed. The findings of existing miRNAs (e.g., miR-21) as well as novel discoveries pertaining to OSCC are also covered. Lastly, we briefly mention the latest findings in targeted gene therapy and the potential use of miRNAs as biomarkers. Our goal is to encourage researchers to further adopt NGS in their studies and give an overview of the latest findings of OSCC treatment.
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Affiliation(s)
| | | | - Young-Seok Park
- Department of Oral Anatomy and Dental Research Institute, School of Dentistry, Seoul National University, Seoul 03968, Korea; (S.K.); (J.W.L.)
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Gleber-Netto FO, Neskey D, Costa AFDM, Kataria P, Rao X, Wang J, Kowalski LP, Pickering CR, Dias-Neto E, Myers JN. Functionally impactful TP53 mutations are associated with increased risk of extranodal extension in clinically advanced oral squamous cell carcinoma. Cancer 2020; 126:4498-4510. [PMID: 32797678 DOI: 10.1002/cncr.33101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 05/24/2020] [Accepted: 06/20/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND The treatment of advanced oral squamous cell carcinoma (OSCC) is a clinical challenge because it is unclear which therapeutic approaches are the best for this highly heterogeneous group of patients. Because TP53 mutations are the most common genetic event in these tumors, the authors investigated whether they could represent an ancillary biomarker in the management of advanced OSCC. METHODS The TP53 gene was sequenced in 78 samples from patients with advanced OSCC who received treatment at 2 institutions located in the United States and Brazil. TP53 mutations were classified according to an in-silico impact score (the evolutionary action score of p53 [EAp53]), which identifies mutations that have greater alterations of p53 protein function (high-risk). Associations between TP53 mutation status/characteristics and clinicopathologic characteristics were investigated. The relevant findings were validated in silico by analyzing 197 samples from patients with advanced OSCC from The Cancer Genome Atlas. RESULTS No differences in clinical outcomes were detected between patients with TP53-mutant and wild-type TP53 disease. However, patients who had tumors carrying high-risk TP53 mutations had a significantly increased risk of developing extranodal extension (ENE) compared with those who had wild-type TP53-bearing tumors. The increased chances of detecting ENE among patients who had high-risk TP53 mutations was validated among patients with advanced OSCC from The Cancer Genome Atlas cohort. CONCLUSIONS High-risk TP53 mutations are associated with an increased chance of detecting ENE in patients with advanced OSCC. Because ENE is 1 of the major factors considered for OSCC patient management, TP53 mutation status may represent a potential ancillary biomarker for treatment decisions regarding postoperative adjuvant therapy.
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Affiliation(s)
- Frederico O Gleber-Netto
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David Neskey
- Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina.,Department of Cell and Molecular Pharmacology and Developmental Therapeutics, Medical University of South Carolina, Charleston, South Carolina
| | - Ana Flávia de Mattos Costa
- Laboratory of Medical Genomics, International Research Center, AC Camargo Cancer Center, Sao Paulo, Brazil
| | - Pranav Kataria
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiayu Rao
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Luiz Paulo Kowalski
- Department of Head and Neck Surgery and Otorhinolaryngology, AC Camargo Cancer Center, Sao Paulo, Brazil
| | - Curtis R Pickering
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.,The University of Texas Graduate School of Biomedical Sciences, Houston, Texas
| | - Emmanuel Dias-Neto
- Laboratory of Medical Genomics, International Research Center, AC Camargo Cancer Center, Sao Paulo, Brazil
| | - Jeffrey N Myers
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.,The University of Texas Graduate School of Biomedical Sciences, Houston, Texas
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Tseng YJ, Wang HY, Lin TW, Lu JJ, Hsieh CH, Liao CT. Development of a Machine Learning Model for Survival Risk Stratification of Patients With Advanced Oral Cancer. JAMA Netw Open 2020; 3:e2011768. [PMID: 32821921 PMCID: PMC7442932 DOI: 10.1001/jamanetworkopen.2020.11768] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
IMPORTANCE A tool for precisely stratifying postoperative patients with advanced oral cancer is crucial for the treatment plan, such as intensifying or deintensifying the regimen to improve their quality of life and prognosis. OBJECTIVE To develop and validate a machine learning-based algorithm that can provide survival risk stratification for patients with advanced oral cancer who have comprehensive clinicopathologic and genetic data. DESIGN, SETTING, AND PARTICIPANTS In this prognostic cohort study, the elastic net penalized Cox proportional hazards regression-based risk stratification model was developed and validated using single-center data collected between January 1, 1996, and December 31, 2011. In total, comprehensive clinicopathologic and genetic data (including clinical, pathologic, and 44 cancer-related gene variant profiles) of 334 patients with stage III or IV oral squamous cell carcinoma were used to develop and validate the algorithm in this 15-year cohort study. Data analysis was conducted between February 1, 2018, and May 6, 2020. MAIN OUTCOMES AND MEASURES The main outcomes were cancer-specific survival, distant metastasis-free survival, and locoregional recurrence-free survival. Model performance was compared in terms of the Akaike information criterion and the Harrell concordance index (C index). RESULTS Complete data were available for 334 patients (315 men; median age at onset, 48 years [interquartile range, 42-56 years]). The predictive models using comprehensive clinicopathologic and genetic data outperformed those using clinicopathologic data alone. In the groups of postoperative patients receiving adjuvant concurrent chemoradiotherapy, the models demonstrated higher classification performance than those using clinicopathologic data alone in cancer-specific survival (mean [SD] C index, 0.689 [0.050] vs 0.673 [0.051]; P = .02) and locoregional recurrence-free survival (mean [SD] C index, 0.693 [0.039] vs 0.678 [0.035]; P = .004). The classification performance in distant metastasis-free survival was not different (mean [SD] C index, 0.702 [0.056] vs 0.688 [0.048]; P = .09). CONCLUSIONS AND RELEVANCE A risk stratification model using comprehensive clinicopathologic and genetic data accurately differentiated the high-risk group from the low-risk group in cancer-specific survival and locoregional recurrence-free survival for postoperative patients with advanced oral cancer. This algorithm could be used through an online calculator to provide additional personalized information for postoperative management of patients with advanced oral squamous cell carcinoma.
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Affiliation(s)
- Yi-Ju Tseng
- Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
- Department of Information Management, Chang Gung University, Taoyuan City, Taiwan
- Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Hsin-Yao Wang
- Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
- PhD Program in Biomedical Engineering, Chang Gung University, Taoyuan City, Taiwan
| | - Ting-Wei Lin
- Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
| | - Jang-Jih Lu
- Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
- School of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan City, Taiwan
| | - Chia-Hsun Hsieh
- School of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
- Division of Hematology-Oncology, Department of Internal Medicine, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan
| | - Chun-Ta Liao
- Department of Head and Neck Oncology Group, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Department of Otorhinolaryngology–Head and Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
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Yang CY, Liu CR, Chang IYF, OuYang CN, Hsieh CH, Huang YL, Wang CI, Jan FW, Wang WL, Tsai TL, Liu H, Tseng CP, Chang YS, Wu CC, Chang KP. Cotargeting CHK1 and PI3K Synergistically Suppresses Tumor Growth of Oral Cavity Squamous Cell Carcinoma in Patient-Derived Xenografts. Cancers (Basel) 2020; 12:cancers12071726. [PMID: 32610557 PMCID: PMC7408003 DOI: 10.3390/cancers12071726] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/23/2020] [Accepted: 06/26/2020] [Indexed: 01/27/2023] Open
Abstract
Oral cavity squamous cell carcinomas (OSCCs) are aggressive tumors, and their recurrence leads to poor prognosis and reduced survival rates. This study aimed to identify therapeutic targets and to evaluate the efficacy of targeted inhibitors in OSCC patient-derived xenograft (PDX) models. Herein, we reported that OSCC PDXs recapitulated the genomic signatures of their paired primary tumors and the expression of CHEK1, PIK3CA, and PIK3CD was significantly upregulated in OSCC. The antitumor efficacy of CHK1 inhibitors (PF477736, AZD7762, LY2606368) and PI3K inhibitors (BYL719, GDC0941, GSK1059615) was investigated in OSCC cell lines and PDX models. Targeting either CHK1 or PI3K effectively inhibited cell proliferation and colony formation by inducing cell cycle arrest and apoptosis in in vitro cell-based assays. Cisplatin-based chemotherapy combined with CHK1 inhibitor treatment synergistically inhibited cell proliferation by suppressing CHK1 phosphorylation and inducing PARP cleavage. Furthermore, compared with monotherapy, cotreatment with CHK1 and PI3K inhibitors exerted synergistic anticancer effects by suppressing CHK1, AKT, and 4E-BP1 phosphorylation. In summary, our study identified CHK1 and PI3K as promising targets, especially in a dual treatment strategy combining a CHK1 inhibitor with cisplatin or a PI3K inhibitor as a novel therapeutic approach for OSCC patients with aberrant cell cycle regulation and PI3K signaling activation.
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Affiliation(s)
- Chia-Yu Yang
- Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (C.-Y.Y.); (C.-R.L.); (F.-W.J.); (W.-L.W.); (T.-L.T.)
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (H.L.); (Y.-S.C.)
- Department of Otolaryngology Head and Neck Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; (I.Y.-F.C.); (C.-N.O.)
| | - Chiao-Rou Liu
- Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (C.-Y.Y.); (C.-R.L.); (F.-W.J.); (W.-L.W.); (T.-L.T.)
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
| | - Ian Yi-Feng Chang
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; (I.Y.-F.C.); (C.-N.O.)
| | - Chun-Nan OuYang
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; (I.Y.-F.C.); (C.-N.O.)
| | - Chia-Hsun Hsieh
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yen-Lin Huang
- Department of Pathology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
| | - Chun-I Wang
- Department of Otolaryngology Head and Neck Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
| | - Fei-Wen Jan
- Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (C.-Y.Y.); (C.-R.L.); (F.-W.J.); (W.-L.W.); (T.-L.T.)
| | - Wan-Ling Wang
- Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (C.-Y.Y.); (C.-R.L.); (F.-W.J.); (W.-L.W.); (T.-L.T.)
| | - Ting-Lin Tsai
- Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (C.-Y.Y.); (C.-R.L.); (F.-W.J.); (W.-L.W.); (T.-L.T.)
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (H.L.); (Y.-S.C.)
| | - Hsuan Liu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (H.L.); (Y.-S.C.)
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; (I.Y.-F.C.); (C.-N.O.)
- Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Ching-Ping Tseng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Yu-Sun Chang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (H.L.); (Y.-S.C.)
- Department of Otolaryngology Head and Neck Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; (I.Y.-F.C.); (C.-N.O.)
| | - Chih-Ching Wu
- Department of Otolaryngology Head and Neck Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; (I.Y.-F.C.); (C.-N.O.)
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Correspondence: (C.-C.W.); or (K.-P.C.)
| | - Kai-Ping Chang
- Department of Otolaryngology Head and Neck Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; (I.Y.-F.C.); (C.-N.O.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Correspondence: (C.-C.W.); or (K.-P.C.)
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Xu L, Zhou C, Pan R, Tang J, Wang J, Li B, Huang T, Duan S, Xu C. PTPN11 hypomethylation is associated with gastric cancer progression. Oncol Lett 2020; 19:1693-1700. [PMID: 32194661 PMCID: PMC7039138 DOI: 10.3892/ol.2020.11250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 10/14/2019] [Indexed: 11/06/2022] Open
Abstract
Protein tyrosine phosphatase non-receptor type 11 (PTPN11) encodes the tyrosine phosphatase SHP-2 that is overexpressed in gastric cancer (GC). In the present study, the association of PTPN11 methylation levels with the incidence of GC and its correlation with SHP-2 overexpression were investigated. The methylation levels of PTPN11 in tumor and adjacent normal tissues of 112 GC patients were assessed by quantitative methylation specific PCR (qMSP). The Cancer Genome Atlas (TCGA) public database was used to analyze the association between PTPN11 methylation and PTPN11 expression. Survival analyses were conducted in order to evaluate the prognostic value of PTPN11 methylation for GC. The results of the qMSP analysis indicated that the methylation levels of PTPN11 in GC tumor tissues were significantly decreased compared with those noted in the normal adjacent tissues (mean with standard deviation: 40.91±26.33 vs. 51.99±37.37, P=0.007). An inverse correlation between PTPN11 methylation levels and PTPN11 mRNA expression levels (P=4×10-6, r=-0.237) was noted. Subgroup analyses indicated that the association of PTPN11 hypomethylation with the incidence of GC was specific to male subjects (P=0.015), heavy drinking patients (P=0.019), patients with poor tumor differentiation (P=0.010) and patients with tumor node and metastasis (TNM) stage III+IV (P=0.008). Kaplan-Meier analyses and log-rank test suggested that PTPN11 hypomethylation was not associated with GC patient overall survival (P=0.605) and recurrence (P=0.485), although it could predict the recurrence of GC patients up to and including 60 years (≤60, P=0.049). The results indicated that PTPN11 levels were hypomethylated in GC patients. TCGA data analysis suggested that PTPN11 hypomethylation could cause an upregulation in the transcription levels of PTPN11. Although, this may explain the pattern of SHP-2 overexpression in GC, additional studies are required to verify this hypothesis. The association of PTPN11 hypomethylation with GC incidence may be specific to male patients, heavy drinking patients, patients with poor tumor differentiation and patients with TNM stage of III+IV. PTPN11 hypomethylation can be considered a biomarker for the recurrence of GC patients with an age of 60 years or lower.
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Affiliation(s)
- Lele Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215200, P.R. China
| | - Cong Zhou
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Ranran Pan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Junjian Tang
- Department of Vascular Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214000, P.R. China
| | - Jinzhi Wang
- Department of Cell Biology, School of Medicine, Soochow University, Suzhou, Jiangsu 215007, P.R. China
| | - Bin Li
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Tianyi Huang
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Shiwei Duan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215200, P.R. China
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Galot R, van Marcke C, Helaers R, Mendola A, Goebbels RM, Caignet X, Ambroise J, Wittouck K, Vikkula M, Limaye N, Machiels JPH. Liquid biopsy for mutational profiling of locoregional recurrent and/or metastatic head and neck squamous cell carcinoma. Oral Oncol 2020; 104:104631. [PMID: 32169746 DOI: 10.1016/j.oraloncology.2020.104631] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 02/18/2020] [Accepted: 03/04/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The molecular landscape of head and neck squamous cell carcinoma (HNSCC) harbors potentially actionable genomic alterations. We aimed to study the utility of liquid biopsy to (i) characterize the mutational landscape of recurrent/metastatic HNSCC using a comprehensive gene panel and (ii) estimate the concordance between DNA mutations identified from circulating tumor DNA (ctDNA) and matched tumor tissues. MATERIALS AND METHODS Targeted next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) of 39 patients with locoregional recurrent (n = 19) and/or metastatic (n = 20) HNSCC. Tumor biopsy (n = 18) was sequenced using the same technique. RESULTS ctDNA was detected in 51% of patients (20/39) with a higher probability of detection in metastatic than locoregional recurrent disease (70% versus 30%, p = 0.025). 81% and 58% of the tissue tumor variants were not detected in plasma when considering all patients and only metastatic patients with detectable ctDNA, respectively. In a multivariate analysis, the likelihood of detecting the tissue tumor variant in plasma was related to metastatic status (p = 0.012), tumor variant allele frequency (p < 0.001) and ctDNA quantity (p < 0.001). 26% of the variants were detected only in liquid and not in the solid biopsy. Three patients without an available tumor sample had plasma containing three different potentially actionable PIK3CA mutations. CONCLUSION CtDNA detection and characterization using targeted NGS is feasible in metastatic HNSCC. Liquid biopsies do not reflect the complete mutation profile of the tumor but have the potential to identify actionable mutations when tumor biopsies are not available as well as variants not found in matched tumor tissue.
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Affiliation(s)
- Rachel Galot
- Department of Medical Oncology, Institut Roi Albert II - Cliniques universitaires Saint-Luc, Brussels, Belgium; Institute for Clinical and Experimental Research (MIRO), Université catholique de Louvain, Brussels, Belgium
| | - Cédric van Marcke
- Department of Medical Oncology, Institut Roi Albert II - Cliniques universitaires Saint-Luc, Brussels, Belgium; Institute for Clinical and Experimental Research (MIRO), Université catholique de Louvain, Brussels, Belgium; Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Raphaël Helaers
- Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Antonella Mendola
- Institute for Clinical and Experimental Research (MIRO), Université catholique de Louvain, Brussels, Belgium
| | - Rose-Marie Goebbels
- Institute for Clinical and Experimental Research (MIRO), Université catholique de Louvain, Brussels, Belgium
| | - Xavier Caignet
- Institute for Clinical and Experimental Research (MIRO), Université catholique de Louvain, Brussels, Belgium
| | - Jérôme Ambroise
- Institute for Clinical and Experimental Research (CTMA), Université catholique de Louvain, Brussels, Belgium
| | - Kyril Wittouck
- Institute for Clinical and Experimental Research (MIRO), Université catholique de Louvain, Brussels, Belgium
| | - Miikka Vikkula
- Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Nisha Limaye
- Genetics of Autoimmune Diseases and Cancer, de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Jean-Pascal H Machiels
- Department of Medical Oncology, Institut Roi Albert II - Cliniques universitaires Saint-Luc, Brussels, Belgium; Institute for Clinical and Experimental Research (MIRO), Université catholique de Louvain, Brussels, Belgium.
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Chen C, Lohavanichbutr P, Zhang Y, Houck JR, Upton MP, Abedi-Ardekani B, Agudo A, Ahrens W, Alemany L, Anantharaman D, Conway DI, Futran ND, Holcatova I, Günther K, Hansen BT, Healy CM, Itani D, Kjaerheim K, Monroe MM, Thomson PJ, Witt BL, Nakoneshny S, Peterson LA, Schwartz SM, Zarins KR, Hashibe M, Brennan P, Rozek LS, Wolf G, Dort JC, Wang P. Prediction of survival of HPV16-negative, p16-negative oral cavity cancer patients using a 13-gene signature: A multicenter study using FFPE samples. Oral Oncol 2020; 100:104487. [PMID: 31835136 PMCID: PMC7386199 DOI: 10.1016/j.oraloncology.2019.104487] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 09/26/2019] [Accepted: 11/21/2019] [Indexed: 12/29/2022]
Abstract
OBJECTIVES To test the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer. MATERIALS AND METHODS Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease. RESULTS Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent. CONCLUSIONS If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients.
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Affiliation(s)
- Chu Chen
- Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA; Department of Epidemiology, University of Washington, 1959 NE Pacific St, Seattle, WA, USA; Department of Otolaryngology -- Head and Neck Surgery, University of Washington, 1959, NE Pacific St, Seattle, WA, USA.
| | - Pawadee Lohavanichbutr
- Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA
| | - Yuzheng Zhang
- Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA
| | - John R Houck
- Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA
| | - Melissa P Upton
- Department of Pathology, University of Washington, 1959 NE Pacific St, Seattle, WA, USA
| | | | - Antonio Agudo
- Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, Avinguda de la Granvia, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Wolfgang Ahrens
- Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany; Institute of Statistics, Bremen University, Achterstraße 30, 28359 Bremen, Germany
| | - Laia Alemany
- Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, Avinguda de la Granvia, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain; Epidemiology and Public Health, Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Devasena Anantharaman
- Rajiv Gandhi Centre for Biotechnology, Melarannoor Road, Thycaud, Thiruvananthapuram, India
| | - David I Conway
- School of Medicine, Dentistry, and Nursing, University of Glasgow, University Avenue, Glasgow, UK
| | - Neal D Futran
- Department of Otolaryngology -- Head and Neck Surgery, University of Washington, 1959, NE Pacific St, Seattle, WA, USA
| | - Ivana Holcatova
- Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Opletalova 38, 110 00 Staré Město, Charles University, Prague, Czech Republic
| | - Kathrin Günther
- Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany
| | - Bo T Hansen
- Cancer Registry of Norway, Ullernchausseen 64, 0379 Oslo, Norway
| | - Claire M Healy
- Dublin Dental University Hospital, Trinity College Dublin, Lincoln Pl, Dublin, Ireland
| | - Doha Itani
- Section of Otolaryngology -- Head & Neck Surgery, Cumming School of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary Alberta, Canada
| | | | - Marcus M Monroe
- University of Utah, 201 Presidents Cir, Salt Lake City, UT, USA
| | - Peter J Thomson
- Oral & Maxillofacial Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Benjamin L Witt
- University of Utah, 201 Presidents Cir, Salt Lake City, UT, USA
| | - Steven Nakoneshny
- Section of Otolaryngology -- Head & Neck Surgery, Cumming School of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary Alberta, Canada
| | | | - Stephen M Schwartz
- Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA; Department of Epidemiology, University of Washington, 1959 NE Pacific St, Seattle, WA, USA
| | - Katie R Zarins
- University of Michigan, 500 S State St, Ann Arbor, MI, USA
| | - Mia Hashibe
- University of Utah, 201 Presidents Cir, Salt Lake City, UT, USA
| | - Paul Brennan
- International Agency of Research on Cancer, 150 Cours Albert Thomas, Lyon, France
| | - Laura S Rozek
- University of Michigan, 500 S State St, Ann Arbor, MI, USA
| | - Gregory Wolf
- University of Michigan, 500 S State St, Ann Arbor, MI, USA
| | - Joseph C Dort
- Section of Otolaryngology -- Head & Neck Surgery, Cumming School of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary Alberta, Canada
| | - Pei Wang
- Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY, USA
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Lin LH, Chang KW, Cheng HW, Liu CJ. SMAD4 Somatic Mutations in Head and Neck Carcinoma Are Associated With Tumor Progression. Front Oncol 2019; 9:1379. [PMID: 31867281 PMCID: PMC6909744 DOI: 10.3389/fonc.2019.01379] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/22/2019] [Indexed: 12/19/2022] Open
Abstract
As the incidence and the mortality rate of head and neck squamous cell carcinoma (HNSCC) is increasing worldwide, gaining knowledge about the genomic changes which happen in the carcinogenesis of HNSCC is essential for the diagnosis and therapy of the disease. SMAD4 (DPC4) is a tumor suppressor gene. It is located at chromosome 18q21.1 and a member of the SMAD family. Which mediates the TGF-β signaling pathway, thereby controlling the growth of epithelial cells. In the study presented here, we analyzed tumor samples by multiplex PCR-based next-generation sequencing (NGS) and found deleterious mutations of SMAD4 in 4.1% of the tumors. Knock-down experiments of endogenous and exogenous SMAD4 expression demonstrated that SMAD4 is involved in the migration and invasion of HNSCC cells. Functional analysis of a missense mutation in the MH1 domain of SMAD4 may be responsible for the loss of function in suppressing tumor progression. Missense SMAD4 mutations, therefore, could be useful prognostic determinants for patients affected by HNSCCs. This report is the first study where NGS analysis based on multiplex-PCR is used to demonstrate the imminent occurrence of missense SMAD4 mutations in HNSCC cells. The gene analysis that we performed may support the identification of SMAD4 mutations as a diagnostic marker or even as a potential therapeutic target in head and neck cancer. Moreover, the analytic strategy proposed for the detection of mutations in the SMAD4 gene may be validated as a platform to assist mutation screening.
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Affiliation(s)
- Li-Han Lin
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Kuo-Wei Chang
- Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Dentistry, Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan
| | - Hui-Wen Cheng
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Chung-Ji Liu
- School of Dentistry, Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.,Department of Oral and Maxillofacial Surgery, Taipei MacKay Memorial Hospital, Taipei, Taiwan
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30
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Batta N, Pandey M. Mutational spectrum of tobacco associated oral squamous carcinoma and its therapeutic significance. World J Surg Oncol 2019; 17:198. [PMID: 31775759 PMCID: PMC6882338 DOI: 10.1186/s12957-019-1741-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 11/04/2019] [Indexed: 12/27/2022] Open
Abstract
Oral squamous cell cancer (OSCC) is a common malignancy attributed to use of chewing smokeless tobacco and smoking. Most of the targeted strategies are based on EGFR expression and mutation; however, none of them has shown significant improvement in survival and response rates. We carried out this study to evaluate mutational profile of tobacco associated oral carcinoma with special emphasis on EGFR and its downstream events. PATIENTS AND METHODS A total of 46 histologically proven cases were recruited between January 2017 and January 2019. Apart from detailed clinical and histological studies, the paraffin-embedded tissue was submitted for expression of 50 genes using Next Generation Sequencing using Ion Ampliseq Cancer Hotspot Panel v2. RESULTS The mean age of patients was 47.8 ± 10.9 years. Majority had tumors on buccal mucosa (24) and tongue (13). Nineteen of these tumors were larger than 4 cm, and 5 had adjacent site involvement. Thirty one were node positive. TP53 mutations were commonest seen in 19 followed by CDKN2A in 11, HRAS in 8, PIK3CA in 3, SMARCB1 in 2, and KIT, EGFR, BRAF, STK11, ABL1, RB1 in one case each. Concomitant TP53 mutation was identified with other mutations like CDKN2A, HRAS, KIT, PIK3CA, STK11, SMARCB1, ABL1, and RB1 making tobacco-associated OSCC as a heterogeneous mutational tumor with multiple events. A patient with TP53 mutations has poor disease free survival (47.4 vs 63% p = 0.17); however, this was not statistically significant. CONCLUSION The study shows a heterogeneous mutational spectrum with multiple mutational events in OSCC. The low EGFR mutation rates and higher mutations in EGFR downstream pathways including that in TP53 and HRAS suggest that anti EGFR strategies may not succeed in these tumors and newer agents and therapeutic combinations need to be tried.
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Affiliation(s)
- Nishant Batta
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005 India
| | - Manoj Pandey
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005 India
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31
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Makarov V, Gorlin A. Meta-analysis of gene expression for development and validation of a diagnostic biomarker panel for Oral Squamous Cell Carcinoma. Comput Biol Chem 2019; 82:74-79. [DOI: 10.1016/j.compbiolchem.2019.06.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 06/11/2019] [Accepted: 06/14/2019] [Indexed: 12/16/2022]
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32
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Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy. Cancers (Basel) 2019; 11:cancers11040445. [PMID: 30934880 PMCID: PMC6521057 DOI: 10.3390/cancers11040445] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/24/2019] [Accepted: 03/26/2019] [Indexed: 12/15/2022] Open
Abstract
About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, TP53 (62%), CCND1 (51%), CDKN2A (30%) and PIK3CA (21%), were not associated with PFS. However, co-occurring CCND1 and CDKN2A mutations were associated with short PFS (HR 2.24, p = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, p = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, p = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring CCND1 and CDKN2A mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies.
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Nakagaki T, Tamura M, Kobashi K, Omori A, Koyama R, Idogawa M, Ogi K, Hiratsuka H, Tokino T, Sasaki Y. Targeted next-generation sequencing of 50 cancer-related genes in Japanese patients with oral squamous cell carcinoma. Tumour Biol 2018; 40:1010428318800180. [PMID: 30226113 DOI: 10.1177/1010428318800180] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Somatic mutation analysis is a standard of practice for human cancers to identify therapeutic sensitization and resistance mutations. We performed a multigene sequencing screen to explore mutational hotspots in cancer-related genes using a semiconductor-based sequencer. DNA from oral squamous cell carcinoma samples was used as a template to amplify 207 regions from 50 cancer-related genes. Of the 80 oral squamous cell carcinoma specimens from Japanese patients, including formalin-fixed paraffin-embedded samples, 56 specimens presented at least one somatic mutation among the 50 investigated genes, and 17 of these samples showed multiple gene somatic mutations. TP53 was the most commonly mutated gene (50.0%), followed by CDKN2A (16.3%), PIK3CA (7.5%), HRAS (5.0%), MET (2.5%), and STK11 (2.5%). In total, 32 cases (40.0%) were human papillomavirus positive and they were significantly less likely to have a TP53, mutation than human papillomavirus-negative oral squamous cell carcinomas (8/32, 25.0% vs 32/48, 66.7%, p = 0.00026). We also detected copy number variations, in which segments of the genome could be duplicated or deleted from the sequencing data. We detected the tumor-specific TP53 mutation in the plasma cell-free DNA from two oral squamous cell carcinoma patients, and after surgery, the test for these mutations became negative. Our approach facilitates the simultaneous high-throughput detection of somatic mutations and copy number variations in oral squamous cell carcinoma samples.
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Affiliation(s)
- Takafumi Nakagaki
- 1 Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan.,2 Department of Oral Surgery, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Miyuki Tamura
- 1 Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - Kenta Kobashi
- 1 Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - Akina Omori
- 1 Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - Ryota Koyama
- 1 Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - Masashi Idogawa
- 1 Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - Kazuhiro Ogi
- 2 Department of Oral Surgery, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Hiroyoshi Hiratsuka
- 2 Department of Oral Surgery, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Takashi Tokino
- 1 Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - Yasushi Sasaki
- 1 Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan.,3 Biology Division, Department of Liberal Arts and Sciences, Center for Medical Education, Sapporo Medical University, Sapporo, Japan
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34
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Ma J, Fu Y, Tu YY, Liu Y, Tan YR, Ju WT, Pickering CR, Myers JN, Zhang ZY, Zhong LP. Mutation allele frequency threshold does not affect prognostic analysis using next-generation sequencing in oral squamous cell carcinoma. BMC Cancer 2018; 18:758. [PMID: 30041611 PMCID: PMC6057048 DOI: 10.1186/s12885-018-4481-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 05/07/2018] [Indexed: 12/11/2022] Open
Abstract
Background With the development of sequencing technologies, there may be some disputes on sequencing analysis. The aim of this study was to investigate different allele frequency thresholds of mutations in targeted genes on prognostic analyses using a panel of cancer associated gene exons (CAGE) in oral squamous cell carcinoma (OSCC). Methods Forty-six patients were included in this study. Twelve genes were sequenced and analyzed using next-generation sequencing from formalin-fixed paraffin-embedded tissues. Allele frequency thresholds of 10, 5, and 3% were used for prognostic analyses. Results With a mean sequence depth of 3199-fold, 99% of CAGE were represented by at least 10 reads. Ninety-four non-synonymous (missense [70.2%], nonsense [11.7%], splice site [10.6%], and insertion/deletion [7.5%]) mutations were detected in 40 OSCC patients with an allele frequency threshold of 10%. TP53 (78.3%), NOTCH1 (30.4%), CASP8 (13.0%), CDKN2A (10.9%), and CDH1 (6.5%) were the most frequently mutated genes. Using allele frequency thresholds of 10, 5, and 3%, there were no significant differences in clinical outcomes between patients with non-synonymous mutations and wild type genotypes. Conclusions TP53, NOTCH1, CASP8, CDKN2A, and CDH1 are the most frequently mutated genes in OSCC patients. The allele frequency threshold used in this study does not affect the results of clinical outcome analysis. Electronic supplementary material The online version of this article (10.1186/s12885-018-4481-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jie Ma
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Yong Fu
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Yao-Yao Tu
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Ying Liu
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Yi-Ran Tan
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Wu-Tong Ju
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Curtis R Pickering
- Department of Head & Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Jeffrey N Myers
- Department of Head & Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Zhi-Yuan Zhang
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China.
| | - Lai-Ping Zhong
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China.
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Kim JY, Cho KH, Lee HY. Effect of Resveratrol on Oral Cancer Cell Invasion Induced by Lysophosphatidic Acid. ACTA ACUST UNITED AC 2018. [DOI: 10.17135/jdhs.2018.18.3.188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Jin Young Kim
- Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Kyung Hwa Cho
- Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Hoi Young Lee
- Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, Korea
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36
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Clues toward precision medicine in oral squamous cell carcinoma: utility of next-generation sequencing for the prognostic stratification of high-risk patients harboring neck lymph node extracapsular extension. Oncotarget 2018; 7:63082-63092. [PMID: 27590518 PMCID: PMC5325348 DOI: 10.18632/oncotarget.11762] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 08/26/2016] [Indexed: 02/03/2023] Open
Abstract
Patients with resected oral squamous cell carcinoma (OSCC) harboring extracapsular extension (ECE) of the involved lymph node, show poor and heterogeneous outcomes. We aim to improve their prognostic stratification by combining genetic information from next-generation sequencing (NGS) using traditional clinicopathological prognosticators. The hotspot mutation regions of 45 cancer-related genes were investigated using NGS with an ultra-deep (>1000×) sequencing approach in formalin-fixed paraffin-embedded samples obtained from 201 patients with resected OSCC harboring ECE. Adjuvant chemoradiotherapy (CRT) and the number of nodes with ECE were the most important traditional prognosticators for disease-specific survival (DSS). The 5-year DSS for patients with CRT versus without, was 55% versus 21% (P < 0.001), and that for 1-3 versus ≥ 4 ECEs was 60% versus 25% (P = 0.001), respectively. Multivariate analysis in patients who received adjuvant CRT for 1-3 ECEs (i.e., those with a favorable expected prognosis) identified the following adverse prognostic factors: 1) margin of < 5 mm for locoregional failure (66% versus 30%, P = 0.007) and DSS (42% versus 63%, P = 0.039); 2) HRAS mutation for distant failure (55% versus 25%, P = 0.007) and DSS (36% versus 63%, P = 0.024); and 3) TP53 DNA-binding domain missense mutations for DSS (52% versus 71%, P = 0.025) and overall survival (39% versus 61%, P = 0.007).We conclude that genetic information from NGS may improve the prognostic stratification offered by traditional prognosticators in resected OSCC patients with ECE. Our findings will contribute to implementation of precision medicine in OSCC patients.
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37
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Blas K, Wilson TG, Tonlaar N, Galoforo S, Hana A, Marples B, Wilson GD. Dual blockade of PI3K and MEK in combination with radiation in head and neck cancer. Clin Transl Radiat Oncol 2018; 11:1-10. [PMID: 30014041 PMCID: PMC6019866 DOI: 10.1016/j.ctro.2018.04.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 04/16/2018] [Accepted: 04/20/2018] [Indexed: 02/07/2023] Open
Abstract
Background and purpose In this study we have combined fractionated radiation treatment (RT) with two molecular targeted agents active against key deregulated signaling pathways in head and neck cancer. Materials and methods We used two molecularly characterized, low passage HNSCC cell lines of differing biological characteristics to study the effects of binimetinib and buparlisib in combination with radiation in vitro and in vivo. Results Buparlisib was active against both cell lines in vitro whereas binimetinib was more toxic to UT-SCC-14. Neither agent modified radiation sensitivity in vitro. Buparlisib significantly inhibited growth of UT-SSC-15 alone or in combination with RT but was ineffective in UT-SCC-14. Binimetinib did cause a significant delay with RT in UT-SCC-14 and it significantly reduced growth of the UT-SCC-15 tumors both alone and with RT. The tri-modality treatment was not as effective as RT with a single effective agent. Conclusions No significant benefit was gained by the combined use of the two agents with RT even though each was efficacious when used alone.
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Affiliation(s)
- Kevin Blas
- Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, United States
| | - Thomas G Wilson
- Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, United States
| | - Nathan Tonlaar
- Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, United States
| | - Sandra Galoforo
- Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, United States
| | - Alaa Hana
- Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, United States
| | - Brian Marples
- Department of Radiation Oncology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - George D Wilson
- Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, United States.,Beaumont BioBank, William Beaumont Hospital, Royal Oak, MI, United States
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38
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Ku BM, Yi SY, Koh J, Bae YH, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. Oncotarget 2018; 7:14803-13. [PMID: 26909611 PMCID: PMC4924753 DOI: 10.18632/oncotarget.7543] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 01/23/2016] [Indexed: 01/07/2023] Open
Abstract
Deletion of CDKN2A (p16) or amplification of CCND1 (cyclin D1) occurs commonly in head and neck squamous cell carcinoma (HNSCC) and induces sustained cyclin-dependent kinase (CDK) 4/6 activation. Here, we report the antiproliferative activity of LY2835219, a selective CDK4/6 inhibitor through inhibition of CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induction of cell cycle arrest in HNSCC cells. In addition, we demonstrated the antitumor effects of HNSCC xenografts to LY2835219 in vivo. Given the limited effect in HNSCC as a single-agent treatment with LY2835219, a combinational strategy is required to enhance antitumor activity. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo. Taken together, our findings suggest that a combinational treatment with LY2835219 and mTOR inhibitor is a promising therapeutic approach for HNSCC.
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Affiliation(s)
- Bo Mi Ku
- Samsung Biomedical Research Institute, Seoul, Korea
| | - Seong Yoon Yi
- Division of Hematology-Oncology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Gyeonggi-do, Korea
| | - Jiae Koh
- Samsung Biomedical Research Institute, Seoul, Korea
| | - Yeon-Hee Bae
- Samsung Biomedical Research Institute, Seoul, Korea
| | - Jong-Mu Sun
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se-Hoon Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Seok Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keunchil Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myung-Ju Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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39
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Dubot C, Bernard V, Sablin MP, Vacher S, Chemlali W, Schnitzler A, Pierron G, Ait Rais K, Bessoltane N, Jeannot E, Klijanienko J, Mariani O, Jouffroy T, Calugaru V, Hoffmann C, Lesnik M, Badois N, Berger F, Le Tourneau C, Kamal M, Bieche I. Comprehensive genomic profiling of head and neck squamous cell carcinoma reveals FGFR1 amplifications and tumour genomic alterations burden as prognostic biomarkers of survival. Eur J Cancer 2018; 91:47-55. [PMID: 29331751 DOI: 10.1016/j.ejca.2017.12.016] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/25/2017] [Accepted: 12/09/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND We aimed at identifying deleterious genomic alterations from untreated head and neck squamous cell carcinoma (HNSCC) patients, and assessing their prognostic value. PATIENTS AND METHODS We retrieved 122 HNSCC patients who underwent primary surgery. Targeted NGS was used to analyse a panel of 100 genes selected among the most frequently altered genes in HNSCC and potential therapeutic targets. We selected only deleterious (activating or inactivating) single nucleotide variations, and copy number variations for analysis. Univariate and multivariate analyses were performed to assess the prognostic value of altered genes. RESULTS A median of 2 (range: 0-10) genomic alterations per sample was observed. Most frequently altered genes involved the cell cycle pathway (TP53 [60%], CCND1 [30%], CDKN2A [25%]), the PI3K/AKT/MTOR pathway (PIK3CA [12%]), tyrosine kinase receptors (EGFR [9%], FGFR1 [5%]) and cell differentiation (FAT1 [7%], NOTCH1 [4%]). TP53 mutations (p = 0.003), CCND1 amplifications (p = 0.04), CDKN2A alterations (p = 0.02) and FGFR1 amplifications (p = 0.003), correlated with shorter overall survival (OS). The number of genomic alterations was significantly higher in the HPV-negative population (p = 0.029) and correlated with a shorter OS (p < 0.0001). Only TP53 mutation and FGFR1 amplification status remained statistically significant in the multivariate analysis. CONCLUSION These results suggest that genomic alterations involving the cell cycle (TP53, CCND1, CDKN2A), as well as FGFR1 amplifications and tumour genomic alterations burden are prognostic biomarkers and might be therapeutic targets for patients with HNSCC.
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Affiliation(s)
- C Dubot
- Department of Medical Oncology, Institut Curie, Paris, Saint-Cloud, France; Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France.
| | - V Bernard
- Unit of Bioinformatics, Next Generation Sequencing Platform-ICGex, Institut Curie, Paris, France
| | - M P Sablin
- Department of Medical Oncology, Institut Curie, Paris, Saint-Cloud, France
| | - S Vacher
- Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France
| | - W Chemlali
- Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France
| | - A Schnitzler
- Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France
| | - G Pierron
- Unit of Somatic Genomics, Department of Genetics, Institut Curie, Paris, France
| | - K Ait Rais
- Unit of Somatic Genomics, Department of Genetics, Institut Curie, Paris, France
| | - N Bessoltane
- Unit of Bioinformatics, Next Generation Sequencing Platform-ICGex, Institut Curie, Paris, France
| | - E Jeannot
- Department of Biopathology, Institut Curie, Paris, France
| | - J Klijanienko
- Department of Biopathology, Institut Curie, Paris, France
| | - O Mariani
- Department of Biopathology, Institut Curie, Paris, France
| | - T Jouffroy
- Department of Surgery, Institut Curie, Paris, France
| | - V Calugaru
- Department of Radiotherapy, Institut Curie, Paris, France
| | - C Hoffmann
- Department of Surgery, Institut Curie, Paris, France
| | - M Lesnik
- Department of Surgery, Institut Curie, Paris, France
| | - N Badois
- Department of Surgery, Institut Curie, Paris, France
| | - F Berger
- Department of Biostatistics, Institut Curie, Paris, France
| | - C Le Tourneau
- Department of Medical Oncology, Institut Curie, Paris, Saint-Cloud, France; INSERM U900 Research Unit, Saint-Cloud, France
| | - M Kamal
- Department of Medical Oncology, Institut Curie, Paris, Saint-Cloud, France
| | - I Bieche
- Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France; EA7331, Paris Descartes University, Faculty of Pharmaceutical and Biological Sciences, Paris, France
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40
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Lapke N, Lu YJ, Liao CT, Lee LY, Lin CY, Wang HM, Ng SH, Chen SJ, Yen TC. Missense mutations in the TP53 DNA-binding domain predict outcomes in patients with advanced oral cavity squamous cell carcinoma. Oncotarget 2018; 7:44194-44210. [PMID: 27283772 PMCID: PMC5190089 DOI: 10.18632/oncotarget.9925] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 05/13/2016] [Indexed: 01/22/2023] Open
Abstract
TP53 mutations have been linked to reduced survival in patients with oral cavity squamous cell carcinoma (OSCC). However, the impact of different types of TP53 mutations remains unclear. Here, we demonstrate that the carriage of missense mutations in the TP53 DNA binding domain (DBD missense mutations) is associated with decreased disease-specific survival (DSS) compared with wild-type TP53 (P=0.002) in a cohort of 345 OSCC patients. In contrast, DSS of patients bearing all of the remaining TP53 mutations did not differ from that observed in wild-type TP53 patients (P=0.955). Our classification method for TP53 mutations was superior to previously reported approaches (disruptive, truncating, Evolutionary Action score, mutations in L2/L3/LSH) for distinguishing between low- and high-risk patients. When analyzed in combination with traditional clinicopathological factors, TP53 DBD missense mutations were an independent prognostic factor for shorter DSS (P=0.014) alongside with advanced AJCC T- and N-classifications and the presence of extracapsular spread. A scoring system that included the four independent prognostic factors allowed a reliable patient stratification into distinct risk groups (high-risk patients, 16.2%). Our results demonstrate the usefulness of TP53 DBD missense mutations combined with clinicopathological factors for improving the prognostic stratification of OSCC patients.
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Affiliation(s)
| | | | - Chun-Ta Liao
- Department of Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
| | - Li-Yu Lee
- Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
| | - Chien-Yu Lin
- Department of Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
| | - Hung-Ming Wang
- Department of Medical Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
| | - Shu-Hang Ng
- Department of Diagnostic Radiology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
| | | | - Tzu-Chen Yen
- Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
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41
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Fadlullah MZH, Chiang IKN, Dionne KR, Yee PS, Gan CP, Sam KK, Tiong KH, Ng AKW, Martin D, Lim KP, Kallarakkal TG, Mustafa WMW, Lau SH, Abraham MT, Zain RB, Rahman ZAA, Molinolo A, Patel V, Gutkind JS, Tan AC, Cheong SC. Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies. Oncotarget 2017; 7:27802-18. [PMID: 27050151 PMCID: PMC5053689 DOI: 10.18632/oncotarget.8533] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 03/18/2016] [Indexed: 12/13/2022] Open
Abstract
Emerging biological and translational insights from large sequencing efforts underscore the need for genetically-relevant cell lines to study the relationships between genomic alterations of tumors, and therapeutic dependencies. Here, we report a detailed characterization of a novel panel of clinically annotated oral squamous cell carcinoma (OSCC) cell lines, derived from patients with diverse ethnicity and risk habits. Molecular analysis by RNAseq and copy number alterations (CNA) identified that the cell lines harbour CNA that have been previously reported in OSCC, for example focal amplications in 3q, 7p, 8q, 11q, 20q and deletions in 3p, 5q, 8p, 18q. Similarly, our analysis identified the same cohort of frequently mutated genes previously reported in OSCC including TP53, CDKN2A, EPHA2, FAT1, NOTCH1, CASP8 and PIK3CA. Notably, we identified mutations (MLL4, USP9X, ARID2) in cell lines derived from betel quid users that may be associated with this specific risk factor. Gene expression profiles of the ORL lines also aligned with those reported for OSCC. By focusing on those gene expression signatures that are predictive of chemotherapeutic response, we observed that the ORL lines broadly clustered into three groups (cell cycle, xenobiotic metabolism, others). The ORL lines noted to be enriched in cell cycle genes responded preferentially to the CDK1 inhibitor RO3306, by MTT cell viability assay. Overall, our in-depth characterization of clinically annotated ORL lines provides new insight into the molecular alterations synonymous with OSCC, which can facilitate in the identification of biomarkers that can be used to guide diagnosis, prognosis, and treatment of OSCC.
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Affiliation(s)
| | - Ivy Kim-Ni Chiang
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.,Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Kalen R Dionne
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.,Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.,Medical Scientist Training Program, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO
| | - Pei San Yee
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
| | - Chai Phei Gan
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
| | - Kin Kit Sam
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
| | - Kai Hung Tiong
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.,Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | | | - Daniel Martin
- Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD, USA
| | - Kue Peng Lim
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
| | - Thomas George Kallarakkal
- Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.,Department of Oro-Maxillofacial Surgery and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | | | - Shin Hin Lau
- Stomatology Unit, Institute for Medical Research, Kuala Lumpur, Malaysia
| | - Mannil Thomas Abraham
- Department of Oral and Maxillofacial Surgery, Tengku Ampuan Rahimah Hospital, Klang, Selangor, Malaysia
| | - Rosnah Binti Zain
- Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.,Department of Oro-Maxillofacial Surgery and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Zainal Ariff Abdul Rahman
- Department of Oro-Maxillofacial Surgery and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Alfredo Molinolo
- Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD, USA
| | - Vyomesh Patel
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
| | - J Silvio Gutkind
- Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD, USA
| | - Aik Choon Tan
- Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Sok Ching Cheong
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.,Department of Oro-Maxillofacial Surgery and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
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42
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Chang PY, Kuo TM, Chen PK, Lin YZ, Hua CH, Chen YC, Ko YC. Arecoline N-Oxide Upregulates Caspase-8 Expression in Oral Hyperplastic Lesions of Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:10197-10205. [PMID: 29092399 DOI: 10.1021/acs.jafc.7b03999] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Areca nut is strongly associated with oral squamous cell carcinoma (OSCC) occurrence. Arecoline N-oxide (ANO), a metabolite of the areca alkaloid arecoline, exhibits an oral fibrotic effect in NOD/SCID mice. Caspase-8, a cysteine protease encoded by the CASP8 gene, is a central mediator in the extrinsic apoptotic pathway via death receptors. Deregulation of caspase-8 in OSCC has been reported. This study investigates the regulation of caspase-8 in ANO-induced oral squamous epithelial hyperplasia that represents the initial highly proliferative stage of oral carcinogenesis. CASP8 somatic mutations were identified from whole-exome sequencing of OSCC samples. Immunohistochemical staining showed upregulation of caspase-8 in ANO-induced hyperplasia of both NOD-SCID and C57BL/6 mice. Levels of expression of CASP8, APAF-1, BAX, and BAD increased in ANO-treated DOK cells. Co-localization of increased caspase-8 and PCNA levels was detected in ANO-induced hyperplastic lesions, whereas no co-localization among γ-H2A.X, caspase-3, and upregulated caspase-8 was observed. The findings indicate that upregulation of caspase-8 is involved in cell proliferation rather than apoptosis during the initial stage of ANO-mediated oral tumorigenesis.
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Affiliation(s)
- Pei-Ying Chang
- Graduate Institute of Clinical Medical Science, China Medical University , Taichung, Taiwan
- Department of Oral and Maxillofacial Surgery, China Medical University Hospital , Taichung, Taiwan
| | - Tzer-Min Kuo
- Environment-Omics-Disease Research Center, China Medical University Hospital and China Medical University , Taichung 40402, Taiwan
| | - Po-Ku Chen
- Environment-Omics-Disease Research Center, China Medical University Hospital and China Medical University , Taichung 40402, Taiwan
| | - You-Zhe Lin
- Graduate Institute of Biomedical Sciences, China Medical University , Taichung, Taiwan
| | - Chun-Hung Hua
- Department of Otorhinolaryngology, China Medical University Hospital , Taichung, Taiwan
| | - Yuan-Chien Chen
- Department of Oral and Maxillofacial Surgery, China Medical University Hospital , Taichung, Taiwan
- School of Dentistry, China Medical University , Taichung, Taiwan
| | - Ying-Chin Ko
- Graduate Institute of Clinical Medical Science, China Medical University , Taichung, Taiwan
- Environment-Omics-Disease Research Center, China Medical University Hospital and China Medical University , Taichung 40402, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University , Taichung, Taiwan
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43
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Sharma V, Nandan A, Sharma AK, Singh H, Bharadwaj M, Sinha DN, Mehrotra R. Signature of genetic associations in oral cancer. Tumour Biol 2017; 39:1010428317725923. [PMID: 29037125 DOI: 10.1177/1010428317725923] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025] Open
Abstract
Oral cancer etiology is complex and controlled by multi-factorial events including genetic events. Candidate gene studies, genome-wide association studies, and next-generation sequencing identified various chromosomal loci to be associated with oral cancer. There is no available review that could give us the comprehensive picture of genetic loci identified to be associated with oral cancer by candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based approaches. A systematic literature search was performed in the PubMed database to identify the loci associated with oral cancer by exclusive candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based study approaches. The information of loci associated with oral cancer is made online through the resource "ORNATE." Next, screening of the loci validated by candidate gene studies and next-generation sequencing approach or by two independent studies within candidate gene studies or next-generation sequencing approaches were performed. A total of 264 loci were identified to be associated with oral cancer by candidate gene studies, genome-wide association studies, and next-generation sequencing approaches. In total, 28 loci, that is, 14q32.33 (AKT1), 5q22.2 (APC), 11q22.3 (ATM), 2q33.1 (CASP8), 11q13.3 (CCND1), 16q22.1 (CDH1), 9p21.3 (CDKN2A), 1q31.1 (COX-2), 7p11.2 (EGFR), 22q13.2 (EP300), 4q35.2 (FAT1), 4q31.3 (FBXW7), 4p16.3 (FGFR3), 1p13.3 (GSTM1-GSTT1), 11q13.2 (GSTP1), 11p15.5 (H-RAS), 3p25.3 (hOGG1), 1q32.1 (IL-10), 4q13.3 (IL-8), 12p12.1 (KRAS), 12q15 (MDM2), 12q13.12 (MLL2), 9q34.3 (NOTCH1), 17p13.1 (p53), 3q26.32 (PIK3CA), 10q23.31 (PTEN), 13q14.2 (RB1), and 5q14.2 (XRCC4), were validated to be associated with oral cancer. "ORNATE" gives a snapshot of genetic loci associated with oral cancer. All 28 loci were validated to be linked to oral cancer for which further fine-mapping followed by gene-by-gene and gene-environment interaction studies is needed to confirm their involvement in modifying oral cancer.
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Affiliation(s)
- Vishwas Sharma
- 1 Department of Health Research, National Institute of Cancer Prevention and Research (NICPR), Noida, India
| | - Amrita Nandan
- 2 Society for Life Science and Human Health, Allahabad, India
| | - Amitesh Kumar Sharma
- 3 Data Management Laboratory, National Institute of Cancer Prevention and Research (NICPR), Noida, India
- 4 Department of Bioinformatics, Indian Council of Medical Research, New Delhi, India
| | - Harpreet Singh
- 3 Data Management Laboratory, National Institute of Cancer Prevention and Research (NICPR), Noida, India
- 4 Department of Bioinformatics, Indian Council of Medical Research, New Delhi, India
| | - Mausumi Bharadwaj
- 1 Department of Health Research, National Institute of Cancer Prevention and Research (NICPR), Noida, India
- 5 Division of Molecular Genetics & Biochemistry
| | - Dhirendra Narain Sinha
- 6 WHO FCTC Global Knowledge Hub on Smokeless Tobacco, National Institute of Cancer Prevention and Research (NICPR), Noida, India
| | - Ravi Mehrotra
- 1 Department of Health Research, National Institute of Cancer Prevention and Research (NICPR), Noida, India
- 3 Data Management Laboratory, National Institute of Cancer Prevention and Research (NICPR), Noida, India
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44
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Chen TW, Lee CC, Liu H, Wu CS, Pickering CR, Huang PJ, Wang J, Chang IYF, Yeh YM, Chen CD, Li HP, Luo JD, Tan BCM, Chan TEH, Hsueh C, Chu LJ, Chen YT, Zhang B, Yang CY, Wu CC, Hsu CW, See LC, Tang P, Yu JS, Liao WC, Chiang WF, Rodriguez H, Myers JN, Chang KP, Chang YS. APOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism. Nat Commun 2017; 8:465. [PMID: 28878238 PMCID: PMC5587710 DOI: 10.1038/s41467-017-00493-9] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 07/04/2017] [Indexed: 12/29/2022] Open
Abstract
Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan. By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13. APOBEC3A expression is significantly higher in tumors carrying APOBEC3B-deletion allele(s). High-level APOBEC3A expression is associated with better overall survival, especially among patients carrying APOBEC3B-deletion alleles, as examined in a second cohort (n = 188; p = 0.004). The frequency of APOBEC3B-deletion alleles is ~50% in 143 genotyped oral squamous cell carcinoma -Taiwan samples (27A3B−/−:89A3B+/−:27A3B+/+), compared to the 5.8% found in 314 OSCC-TCGA samples. We thus report a frequent APOBEC mutational profile, which relates to a APOBEC3B-deletion germline polymorphism in Taiwanese oral squamous cell carcinoma that impacts expression of APOBEC3A, and is shown to be of clinical prognostic relevance. Our finding might be recapitulated by genomic studies in other cancer types. Oral squamous cell carcinoma is a prevalent malignancy in Taiwan. Here, the authors show that OSCC in Taiwanese show a frequent deletion polymorphism in the cytidine deaminases gene cluster APOBEC3 resulting in increased expression of A3A, which is shown to be of clinical prognostic relevance.
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Affiliation(s)
- Ting-Wen Chen
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Bioinformatics Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Chi-Ching Lee
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Bioinformatics Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department and Graduate Institute of Computer Science and Information Engineering, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Hsuan Liu
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Graduate Institute of Biomedical Sciences, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department of Biochemistry, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Linkou, Gueishan, Taoyuan, 33305, Taiwan
| | - Chi-Sheng Wu
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan
| | - Curtis R Pickering
- Departments of Head and Neck Surgery, the University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA
| | - Po-Jung Huang
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Bioinformatics Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department of Biomedical Sciences, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan
| | - Jing Wang
- Departments of Biostatistics, the University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA
| | - Ian Yi-Feng Chang
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Bioinformatics Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Yuan-Ming Yeh
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Bioinformatics Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Chih-De Chen
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Hsin-Pai Li
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Graduate Institute of Biomedical Sciences, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department of Microbiology and Immunology, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan
| | - Ji-Dung Luo
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Bioinformatics Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Bertrand Chin-Ming Tan
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Graduate Institute of Biomedical Sciences, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department of Biomedical Sciences, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan
| | - Timothy En Haw Chan
- Graduate Institute of Biomedical Sciences, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Chuen Hsueh
- Pathology Core of the Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department of Pathology, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan
| | - Lichieh Julie Chu
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Liver Research Center, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan
| | - Yi-Ting Chen
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Graduate Institute of Biomedical Sciences, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department of Biomedical Sciences, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Bing Zhang
- Department of Molecular and Human Genetics Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, 77030, USA
| | - Chia-Yu Yang
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Linkou, Gueishan, Taoyuan, 33305, Taiwan.,Department of Microbiology and Immunology, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Chih-Ching Wu
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan.,Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Chia-Wei Hsu
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Lai-Chu See
- Department of Public Health, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Biostatistics Core Laboratory, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Petrus Tang
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Bioinformatics Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Molecular Regulation and Bioinformatics Laboratory, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Molecular Infectious Diseases Research Center, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan
| | - Jau-Song Yu
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Liver Research Center, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan.,Department of Cell and Molecular Biology, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan
| | - Wei-Chao Liao
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.,Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan
| | - Wei-Fan Chiang
- Department of Oral & Maxillofacial Surgery, Chi-Mei Medical Center, Liouying, 736, Taiwan.,School of Dentistry, National Yang Ming University, Taipei, 112, Taiwan
| | - Henry Rodriguez
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Jeffrey N Myers
- Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan
| | - Kai-Ping Chang
- Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan. .,College of Medicine, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan.
| | - Yu-Sun Chang
- Molecular Medicine Research Center, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan. .,Graduate Institute of Biomedical Sciences, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan. .,Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Gueishan, Taoyuan, 33305, Taiwan.
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45
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Makarev E, Schubert AD, Kanherkar RR, London N, Teka M, Ozerov I, Lezhnina K, Bedi A, Ravi R, Mehra R, Hoque MO, Sloma I, Gaykalova DA, Csoka AB, Sidransky D, Zhavoronkov A, Izumchenko E. In silico analysis of pathways activation landscape in oral squamous cell carcinoma and oral leukoplakia. Cell Death Discov 2017; 3:17022. [PMID: 28580171 PMCID: PMC5439156 DOI: 10.1038/cddiscovery.2017.22] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 02/23/2017] [Accepted: 03/13/2017] [Indexed: 12/16/2022] Open
Abstract
A subset of patients with oral squamous cell carcinoma (OSCC), the most common subtype of head and neck squamous cell carcinoma (HNSCC), harbor dysplastic lesions (often visually identified as leukoplakia) prior to cancer diagnosis. Although evidence suggest that leukoplakia represents an initial step in the progression to cancer, signaling networks driving this progression are poorly understood. Here, we applied in silico Pathway Activation Network Decomposition Analysis (iPANDA), a new bioinformatics software suite for qualitative analysis of intracellular signaling pathway activation using transcriptomic data, to assess a network of molecular signaling in OSCC and pre-neoplastic oral lesions. In tumor samples, our analysis detected major conserved mitogenic and survival signaling pathways strongly associated with HNSCC, suggesting that some of the pathways identified by our algorithm, but not yet validated as HNSCC related, may be attractive targets for future research. While pathways activation landscape in the majority of leukoplakias was different from that seen in OSCC, a subset of pre-neoplastic lesions has demonstrated some degree of similarity to the signaling profile seen in tumors, including dysregulation of the cancer-driving pathways related to survival and apoptosis. These results suggest that dysregulation of these signaling networks may be the driving force behind the early stages of OSCC tumorigenesis. While future studies with larger leukoplakia data sets are warranted to further estimate the values of this approach for capturing signaling features that characterize relevant lesions that actually progress to cancers, our platform proposes a promising new approach for detecting cancer-promoting pathways and tailoring the right therapy to prevent tumorigenesis.
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Affiliation(s)
- Eugene Makarev
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD 21218, USA
| | - Adrian D Schubert
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | | | - Nyall London
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Mahder Teka
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD 21218, USA
| | - Ivan Ozerov
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD 21218, USA
| | - Ksenia Lezhnina
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD 21218, USA
| | - Atul Bedi
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Rajani Ravi
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Rannee Mehra
- Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Mohammad O Hoque
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Ido Sloma
- R&D, Champions Oncology, Baltimore, MD, USA
| | - Daria A Gaykalova
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Antonei B Csoka
- Department of Anatomy, Howard University, Washington, DC, USA
| | - David Sidransky
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Alex Zhavoronkov
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD 21218, USA.,D. Rogachev Federal Research and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Samory Mashela 1, Moscow 117997, Russia.,The Biogerontology Research Foundation, 2354 Chynoweth House, Trevissome Park, Truro TR4 8UN, UK
| | - Evgeny Izumchenko
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
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Tamura T, Ichikawa T, Nakahata S, Kondo Y, Tagawa Y, Yamamoto K, Nagai K, Baba T, Yamaguchi R, Futakuchi M, Yamashita Y, Morishita K. Loss of NDRG2 Expression Confers Oral Squamous Cell Carcinoma with Enhanced Metastatic Potential. Cancer Res 2017; 77:2363-2374. [PMID: 28209617 DOI: 10.1158/0008-5472.can-16-2114] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/04/2016] [Accepted: 01/16/2017] [Indexed: 11/16/2022]
Abstract
Loss of the tumor suppressor NDRG2 has been implicated in the development of oral squamous cell carcinoma (OSCC), acting by modulating PI3K/AKT-mediated dephosphorylation of PTEN at S380/S382/T383 (STT). Here, we show that the majority of OSCC tumors with lymph node metastasis, a major prognostic factor, exhibit high levels of phosphorylated AKT-S473 and PTEN-STT and low levels of NDRG2 expression. In Ndrg2-deficient mice, which develop a wide range of tumors, we developed a model of OSCC by treatment with the tobacco surrogate 4-nitroquinoline-1-oxide (4-NQO). In this model, both the number and size of OSCC tumors were increased significantly by Ndrg2 deficiency, which also increased invasion of cervical lymph nodes. 4-NQO treatment of human OSCC cell lines exhibiting low NDRG2 expression induced epithelial-mesenchymal transition via activation of NF-κB signaling. Conversely, ectopic expression of NDRG2 reversed the EMT phenotype and inhibited NF-κB signaling via suppression of PTEN-STT and AKT-S473 phosphorylation. Our results show how NDRG2 expression serves as a critical determinant of the invasive and metastatic capacity of OSCC. Cancer Res; 77(9); 2363-74. ©2017 AACR.
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Affiliation(s)
- Tomohiro Tamura
- Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Tomonaga Ichikawa
- Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Shingo Nakahata
- Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Yudai Kondo
- Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Yuri Tagawa
- Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Koji Yamamoto
- Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Kentaro Nagai
- Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Takashi Baba
- Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Ryoji Yamaguchi
- Laboratory of Veterinary Pathology, Department of Veterinary, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan
| | - Mitsuru Futakuchi
- Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yoshihiro Yamashita
- Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Kazuhiro Morishita
- Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
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47
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Liao CT, Wen YW, Lee SR, Liu TW, Tsai ST, Tsai MH, Lin JC, Lou PJ, Chu PY, Leu YS, Tsai KY, Terng SD, Chen TM, Wang CH, Chien CY, Chen WC, Lee LY, Lin CY, Wang HM, Ng SH, Lin CH, Fang TJ, Huang SF, Kang CJ, Chang KP, Yang LY, Yen TC. Clinical Outcomes of Taiwanese Patients with cT4 Oral Cavity Squamous Cell Carcinoma: Toward the Identification of the Optimal Initial Treatment Approach for cT4b Patients. Ann Surg Oncol 2016; 24:785-793. [DOI: 10.1245/s10434-016-5629-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Indexed: 11/18/2022]
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48
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Li Y, Sturgis EM, Yuan Y, Lu M, Cao X, Wei Q, Li G. Effect of human papillomavirus seropositivity and E2F2 promoter variants on risk of squamous cell carcinomas of oropharynx and oral cavity. Carcinogenesis 2016; 37:1070-1078. [PMID: 27609456 PMCID: PMC5091040 DOI: 10.1093/carcin/bgw095] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 08/29/2016] [Accepted: 08/30/2016] [Indexed: 01/09/2023] Open
Abstract
Given roles of HPV and genetic factors in cancer risk, we evaluated associations of HPV16 seropositivity and five E2F2 promoter variants with squamous cell carcinoma of oropharynx (SCCOP) and squamous cell carcinoma of oral cavity (SCCOC) risk in a case-control study of 325 patients and 335 cancer-free matched controls. We found that HPV16 seropositivity was significantly associated with SCCOP risk (aOR, 5.4, 95%CI, 3.7-8.9) but not SCCOC (aOR, 0.8, 95%CI, 0.4-1.5), while each E2F2 polymorphism had no significant main effect on SCCOP and SCCOC risk. However, after combining HPV serological status and E2F2 promoter variants together, the modification effect of HPV serology and individual or combined risk genotypes of five polymorphisms on risk was significantly higher among SCCOP than among SCCOC. Furthermore, the stratified analysis by smoking status showed that all such modifying effects aforementioned on SCCOP were more pronounced in never smokers than in smokers. These findings are in agreement with those of previous studies, in which a majority of SCCOP were caused by HPV infection, whereas most SCCOC were found to be caused by smoking and drinking. Taken together, these findings indicate that the risk of SCCOP as opposed to SCCOC associated with HPV16 seropositivity was modified by E2F2 promoter variants either individually or jointly, especially in never smokers.
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Affiliation(s)
- Yuncheng Li
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Erich M. Sturgis
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ying Yuan
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Meixia Lu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Epidemiology and Biostatistics, School of Public Health, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaoli Cao
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Ultrasound, Yantai Yuhuangding Hospital, Yantai 264000, China and
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Guojun Li
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Michmerhuizen NL, Birkeland AC, Bradford CR, Brenner JC. Genetic determinants in head and neck squamous cell carcinoma and their influence on global personalized medicine. Genes Cancer 2016; 7:182-200. [PMID: 27551333 PMCID: PMC4979591 DOI: 10.18632/genesandcancer.110] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
While sequencing studies have provided an improved understanding of the genetic landscape of head and neck squamous cell carcinomas (HNSCC), there remains a significant lack of genetic data derived from non-Caucasian cohorts. Additionally, there is wide variation in HNSCC incidence and mortality worldwide both between and within various geographic regions. These epidemiologic differences are in part accounted for by varying exposure to environmental risk factors such as tobacco, alcohol, high risk human papilloma viruses and betel quid. However, inherent genetic factors may also play an important role in this variability. As limited sequencing data is available for many populations, the involvement of unique genetic factors in HNSCC pathogenesis from epidemiologically diverse groups is unknown. Here, we review current knowledge about the epidemiologic, environmental, and genetic variation in HNSCC cohorts globally and discuss future studies necessary to further our understanding of these differences. Long-term, a more complete understanding of the genetic drivers found in diverse HNSCC cohorts may help the development of personalized medicine protocols for patients with rare or complex genetic events.
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Affiliation(s)
- Nicole L Michmerhuizen
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Andrew C Birkeland
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Carol R Bradford
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - J Chad Brenner
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
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Er TK, Su YF, Wu CC, Chen CC, Wang J, Hsieh TH, Herreros-Villanueva M, Chen WT, Chen YT, Liu TC, Chen HS, Tsai EM. Targeted next-generation sequencing for molecular diagnosis of endometriosis-associated ovarian cancer. J Mol Med (Berl) 2016; 94:835-47. [PMID: 26920370 DOI: 10.1007/s00109-016-1395-2] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 01/21/2016] [Accepted: 01/25/2016] [Indexed: 12/22/2022]
Abstract
UNLABELLED Recent molecular and pathological studies suggest that endometriosis may serve as a precursor of ovarian cancer (endometriosis-associated ovarian cancer, EAOC), especially of the endometrioid and clear cell subtypes. Accordingly, this study had two cardinal aims: first, to obtain mutation profiles of EAOC from Taiwanese patients; and second, to determine whether somatic mutations present in EAOC can be detected in preneoplastic lesions. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from ten endometriosis patients with malignant transformation. Macrodissection was performed to separate four different types of cells from FFPE sections in six patients. The four types of samples included normal endometrium, ectopic endometriotic lesion, atypical endometriosis, and carcinoma. Ultra-deep (>1000×) targeted sequencing was performed on 409 cancer-related genes to identify pathogenic mutations associated with EAOC. The most frequently mutated genes were PIK3CA (6/10) and ARID1A (5/10). Other recurrently mutated genes included ETS1, MLH1, PRKDC (3/10 each), and AMER1, ARID2, BCL11A, CREBBP, ERBB2, EXT1, FANCD2, MSH6, NF1, NOTCH1, NUMA1, PDE4DIP, PPP2R1A, RNF213, and SYNE1 (2/10 each). Importantly, in five of the six patients, identical somatic mutations were detected in atypical endometriosis and tumor lesions. In two patients, genetic alterations were also detected in ectopic endometriotic lesions, indicating the presence of genetic alterations in preneoplastic lesion. Genetic analysis in preneoplastic lesions may help to identify high-risk patients at early stage of malignant transformation and also shed new light on fundamental aspects of the molecular pathogenesis of EAOC. KEY MESSAGES Molecular characterization of endometriosis-associated ovarian cancer genes by targeted NGS. Candidate genes predictive of malignant transformation were identified. Chromatin remodeling, PI3K-AKT-mTOR, Notch signaling, and Wnt/β-catenin pathway may promote cell malignant transformation.
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Affiliation(s)
- Tze-Kiong Er
- Department of Health and Nutrition Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan.,Division of Molecular Diagnostics, Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Fa Su
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chun-Chieh Wu
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chih-Chieh Chen
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Jing Wang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Tsung-Hua Hsieh
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Marta Herreros-Villanueva
- Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco UPV/EHU, San Sebastián, Spain
| | - Wan-Tzu Chen
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Ting Chen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ta-Chih Liu
- Division of Molecular Diagnostics, Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Hung-Sheng Chen
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Eing-Mei Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. .,Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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