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Michikawa C, Torres-Saavedra PA, Silver NL, Harari PM, Kies MS, Rosenthal DI, Le QT, Jordan RC, Duose DY, Mallampati S, Trivedi S, Luthra R, Wistuba II, Osman AA, Lichtarge O, Foote RL, Parvathaneni U, Hayes DN, Pickering CR, Myers JN. Evolutionary Action Score of TP53 Analysis in Pathologically High-Risk Human Papillomavirus-Negative Head and Neck Cancer From a Phase 2 Clinical Trial: NRG Oncology Radiation Therapy Oncology Group 0234. Adv Radiat Oncol 2022; 7:100989. [PMID: 36420184 PMCID: PMC9677209 DOI: 10.1016/j.adro.2022.100989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 05/04/2022] [Indexed: 12/15/2022] Open
Abstract
Purpose An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations stratifies patients with head and neck squamous cell carcinoma (HNSCC) bearing TP53 missense mutations as high-risk, associated with poor outcomes, or low-risk, with similar outcomes as TP53 wild-type, and has been validated as a reliable prognostic marker. We performed this study to further validate prior findings demonstrating that EAp53 is a prognostic marker for patients with locally advanced HNSCC and explored its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy. Methods and Materials Eighty-one resection samples from patients treated surgically for stage III or IV human papillomavirus-negative HNSCC with high-risk pathologic features, who received either radiation therapy + cetuximab + cisplatin (cisplatin) or radiation therapy + cetuximab + docetaxel (docetaxel) as adjuvant treatment in a phase 2 study were subjected to TP53 targeted sequencing and EAp53 scoring to correlate with clinical outcomes. Due to the limited sample size, patients were combined into 2 EAp53 groups: (1) wild-type or low-risk; and (2) high-risk or other. Results At a median follow-up of 9.8 years, there was a significant interaction between EAp53 group and treatment for overall survival (P = .008), disease-free survival (P = .05), and distant metastasis (DM; P = .004). In wild-type or low-risk group, the docetaxel arm showed significantly better overall survival (hazard ratio [HR] 0.11, [0.03-0.36]), disease-free survival (HR 0.24, [0.09-0.61]), and less DM (HR 0.04, [0.01-0.31]) than the cisplatin arm. In high-risk or other group, differences between treatments were not statistically significant. Conclusions The docetaxel arm was associated with better survival than the cisplatin arm for patients with wild-type or low-risk EAp53. These benefits appear to be largely driven by a reduction in DM.
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Affiliation(s)
- Chieko Michikawa
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas,Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Pedro A. Torres-Saavedra
- NRG Oncology Statistics and Data Management Center, American College of Radiology, Philadelphia, Pennsylvania
| | - Natalie L. Silver
- Cleveland Clinic, Head and Neck Institute/Lerner Research Institute, Cleveland, Ohio
| | - Paul M. Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Merrill S. Kies
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David I. Rosenthal
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Quynh-Thu Le
- Department of Radiation Oncology, Stanford University Medical Center, Stanford, California
| | - Richard C. Jordan
- NRG Oncology Biospecimen Bank and University of California, San Francisco, San Francisco, California
| | | | | | - Sanchit Trivedi
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rajyalakshmi Luthra
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Abdullah A. Osman
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Olivier Lichtarge
- Departments of Molecular and Human Genetics, Pharmacology, and Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas
| | - Robert L. Foote
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Upendra Parvathaneni
- Radiation Oncology Center, University of Washington Medical Center, Seattle, Washington
| | - D. Neil Hayes
- Division of Medical Oncology, The University of Tennessee Health Science Center, Memphis, Tennessee
| | - Curtis R. Pickering
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeffrey N. Myers
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas,Corresponding author: Jeffrey N. Myers, MD, PhD
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Osawa Y, Aoyama KI, Hosomichi K, Uchibori M, Tajima A, Kimura M, Ota Y. Somatic mutations in oral squamous cell carcinomas in 98 Japanese patients and their clinical implications. Cancer Treat Res Commun 2021; 29:100456. [PMID: 34563788 DOI: 10.1016/j.ctarc.2021.100456] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 11/29/2022]
Abstract
INTRODUCTION The somatic mutational profile of oral squamous cell carcinoma (OSCC) among Japanese patients has been less investigated, partly because of the rarity of the tumor. Moreover, previous studies have either used formalin-fixed paraffin-embedded samples or lacked paired normal tissues. We aimed to determine somatic mutations in the exomes of 76 genes, including 50 driver genes of solid cancers and NOTCH-related genes, some of which are previously reported as frequently mutated in head and neck squamous cell carcinoma or OSCC. MATERIALS AND METHODS We used fresh-frozen tumor/normal-paired samples from 98 treatment-naïve Japanese patients with OSCC and analyzed their correlations with clinicopathological characteristics and survival. RESULTS We identified 136 exonic mutations, including 78 non-synonymous mutations, 13 synonymous mutations, 22 nonsense mutations, 2 non-frameshift deletions, 11 frameshift deletion, and 5 each of splice-site and frameshift insertions. The most frequently mutated genes were TP53 (36.7%), FAT1 (9.2%), NOTCH1 (8.2%), CDKN2A (7.1%), ZFHX4 (5.1%), CASP8 (4.1%), EP300 (4.1%), and KMT2D (4.1%). We followed up 90 of the 98 patients for 3 years. Among them, TP53 mutation was associated with significantly shorter 3-year disease-free survival. Most of the identified TP53 mutations occurred in the DNA-binding domain and were functionally deleterious. DISCUSSION Our findings and the mutation spectra can contribute to the development of a therapeutic strategy for Japanese patients with OSCC.
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Affiliation(s)
- Yuko Osawa
- Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine,143 Shimokasuya, Isehara, Kanagawa, Japan
| | - Ken-Ichi Aoyama
- Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine,143 Shimokasuya, Isehara, Kanagawa, Japan
| | - Kazuyoshi Hosomichi
- The Institute of Medical Sciences, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, Japan
| | - Masahiro Uchibori
- Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine,143 Shimokasuya, Isehara, Kanagawa, Japan
| | - Atsushi Tajima
- Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, Japan
| | - Minoru Kimura
- The Institute of Medical Sciences, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, Japan
| | - Yoshihide Ota
- Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine,143 Shimokasuya, Isehara, Kanagawa, Japan.
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Stepan KO, Li MM, Kang SY, Puram SV. Molecular margins in head and neck cancer: Current techniques and future directions. Oral Oncol 2020; 110:104893. [PMID: 32702629 DOI: 10.1016/j.oraloncology.2020.104893] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 07/01/2020] [Indexed: 12/14/2022]
Abstract
Complete tumor extirpation with clear surgical margins remains a central tenet of oncologic head and neck surgery. Rates of locoregional recurrence and survival are both significantly worse when clear margins are unable to be obtained. Current clinical practice relies on the use of frozen sections intra-operatively, followed by traditional histopathologic analysis post-operatively to assess the surgical margin. However, with improved understanding of tumor biology and advances in technology, new techniques have emerged to analyze margins at a molecular level. Such molecular margin analysis interrogates tissue for genetic, epigenetic, or proteomic changes that may belie tumor presence or aggressive features not captured by standard histopathologic techniques. Intra-operatively, this information may be used to guide resection, while post-operatively, it may help to stratify patients for adjuvant treatment. In this review, we summarize the current state of molecular margin analysis and describe directions for future research.
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Affiliation(s)
- Katelyn O Stepan
- Department of Otolaryngology - Head and Neck Surgery, Washington University School of Medicine, 4921 Parkview Pl, St. Louis, MO 63110, USA
| | - Michael M Li
- Department of Otolaryngology - Head and Neck Surgery, Ohio State University Wexner Medical Center, 410 W. 10(th) Ave, Columbus, OH, USA
| | - Stephen Y Kang
- Department of Otolaryngology - Head and Neck Surgery, Ohio State University Wexner Medical Center, 410 W. 10(th) Ave, Columbus, OH, USA
| | - Sidharth V Puram
- Department of Otolaryngology - Head and Neck Surgery, Washington University School of Medicine, 4921 Parkview Pl, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 4921 Parkview Pl, St. Louis, MO 63110, USA.
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Devaraja K, Aggarwal S, Verma SS, Gupta SC. Clinico-pathological peculiarities of human papilloma virus driven head and neck squamous cell carcinoma: A comprehensive update. Life Sci 2020; 245:117383. [PMID: 32007572 DOI: 10.1016/j.lfs.2020.117383] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/17/2020] [Accepted: 01/28/2020] [Indexed: 01/11/2023]
Abstract
AIMS The current article provides a detailed account of the current understanding of molecular and clinico-pathological aspects of Human papilloma virus (HPV) driven head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS The literature review included most of the landmark trials and clinical studies related to the HPV driven HNSCC. KEY FINDINGS HPV positive HNSCC differ distinctly from HPV negative tobacco-related HNSCC, especially in oropharyngeal region. Therefore, the American joint committee on cancer`s latest manual for classification and staging of cancer suggests a separate staging system for HPV positive oropharyngeal cancers. Despite the younger patients being affected and the high propensity for cervical metastasis, the HPV positive oropharyngeal cancers respond much better to the treatment. The association with wild type TP53 and low EGFR expression confers the favorable prognosis in HPV driven HNSCC. Since the association is not universal, we suggest checking for p53 and EGFR expression status before considering de-intensification of therapy. In addition, the presence of matted lymph nodes and five or more nodes could mean relatively poorer prognosis, and are not suitable for de-intensification of therapy. The same is also true probably with higher T stage and co-existing tobacco use. The methods for the detection of p16, HPV DNA, HPV E6/E7 mRNA, anti-E6/E7 antibodies, in tissue, in serum and in saliva of patients, along with their clinical implications are also discussed. SIGNIFICANCE This article provides latest developments on the HPV driven HNSCC. 'Diagnosis of transcriptionally active HPV infection,' 'Modalities for surveillance,' 'Implication of de-escalation of therapy' are some of the critical issues that could serve the medical, the research as well as the patient communities.
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Affiliation(s)
- K Devaraja
- Department of Otorhinolaryngology and Head and Neck surgery, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, 576104, India.
| | - Sadhna Aggarwal
- Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sumit Singh Verma
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India
| | - Subash Chandra Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India.
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Time series analysis of TP53 gene mutations in recurrent HPV-negative vulvar squamous cell carcinoma. Mod Pathol 2019; 32:415-422. [PMID: 30291345 DOI: 10.1038/s41379-018-0141-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/10/2018] [Accepted: 08/14/2018] [Indexed: 01/16/2023]
Abstract
The impact of TP53 gene mutations in recurrent HPV-negative vulvar squamous cell carcinomas is unclear. TP53 gene mutations were analyzed in archival tissues of 24 primary squamous cell carcinoma and local vulvar recurrences arising in chronic inflammatory dermatoses by analyzing the full coding sequence of the TP53 gene and correlated with disease-free survival. After resection of the primary squamous cell carcinoma with clear margins 19/24 patients had one and 5/24 had multiple recurrences. The first recurrence occurred after median of 46 months (range 12-180 months). In all, 17/24 (71%) primary squamous cell carcinomas had TP53 gene mutations and recurred after median disease-free intervals of 33 months (range 12-180). 14/17 (88%) recurrent squamous cell carcinomas carried again TP53 gene mutations, five with identical and nine with different, more complex TP53 gene mutations. 7/24 (29%) patients with a p53 wild-type primary SCC had the first recurrence after median 65 months (range 14-144) featuring p53 wild-type in 3/7 (43%) and TP53 gene mutations in 4/7 (57%) recurrent squamous cell carcinomas. Disease-free intervals of > 5 years (60-180 months) were observed in 10/24 patients total (42%; equally divided among p53 wild-type (5/7; 71%) and TP53 gene mutated (5/17; 29%) squamous cell carcinomas). In summary, squamous cell carcinomas recurred in the residual vulvar dermatosis independent of TP53 gene mutational status of the primary squamous cell carcinoma. The majority of TP53 gene mutated cancers recurred with different TP53 gene mutations, some of them more complex, and patients with p53 wild type developed TP53 gene mutations in the recurrent squamous cell carcinomas, possibly indicating increased genetic instability in longstanding chronic inflammatory dermatoses. A change of TP53 gene mutational status after > 5 years suggests de novo oncogenic events/carcinogenesis. Longer disease-free intervals in patients with p53 wild-type primary squamous cell carcinoma suggest that TP53 gene mutational status may serve as a prognostic marker for disease-free intervals.
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Metheetrairut C, Chotigavanich C, Amornpichetkul K, Keskool P, Ongard S, Metheetrairut C. Expression levels of miR-34-family microRNAs are associated with TP53 mutation status in head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 2018; 276:521-533. [PMID: 30515607 DOI: 10.1007/s00405-018-5223-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 11/26/2018] [Indexed: 01/07/2023]
Abstract
PURPOSE The majority of head and neck squamous cell carcinoma (HNSCC) cases in developing countries are associated with cigarette smoking and TP53 mutations. p53 is a transcription factor that activates downstream genes, including the hsa-miR-34a and hsa-miR-34b/c loci, to achieve cell-cycle arrest, senescence, and/or apoptosis. This study examined the differences in expression levels of miR-34 in HNSCC with or without TP53 mutations. METHODS We examined surgically resected tumor samples and normal adjacent tissues from HNSCC in oral cavity, larynx, and hypopharynx for TP53 mutations (exons 5-8) and miR-34 expression levels. RESULTS miR-34a, miR-34b, miR-34b*, and miR-34c are significantly up-regulated in tumors with wild-type TP53 genes (n = 23); while such up-regulation is not observed in tumors with mutant TP53 (n = 19). Although expression levels of miR-34-family miRNAs do not correlate with gender, age, or tumor staging, interestingly they are correlated with smoking status and tumor sites. miR-34b/b*/c are up-regulated in tumors from those who ever smoked or recently smoked (quit smoking less than 15 years ago); but such up-regulation was not seen in those who never smoked or quit smoking for at least 15 years. HNSCC of the oral cavity also up-regulated miR-34b/b*/c while no such overexpression was observed in HNSCC of the larynx and hypopharynx. CONCLUSIONS Surgically resected HNSCC samples with no TP53 mutations have elevated levels of miR-34a and miR-34b/b*/c, while those with TP53 mutations show no such up-regulation. miR-34b/b*/c expression is also correlated with smoking status and tumor sites.
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Affiliation(s)
- Chanatip Metheetrairut
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Srisavarindhira Building, 2 Wanglang Rd., Bangkok Noi, Bangkok, 10700, Thailand.
| | - Chanticha Chotigavanich
- Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kanchana Amornpichetkul
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Phawin Keskool
- Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Sunun Ongard
- Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Choakchai Metheetrairut
- Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Mutational profiling can identify laryngeal dysplasia at risk of progression to invasive carcinoma. Sci Rep 2018; 8:6613. [PMID: 29700339 PMCID: PMC5919930 DOI: 10.1038/s41598-018-24780-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 04/10/2018] [Indexed: 02/07/2023] Open
Abstract
Early diagnosis of laryngeal squamous cell carcinoma (LSCC) at the stage of dysplasia could greatly improve the outcome of affected patients. For the first time we compared the mutational landscape of non-progressing dysplasia (NPD; n = 42) with progressing dysplasia (PD; n = 24), along with patient-matched LSCC biopsies; a total of 90 samples. Using targeted next-generation sequencing identified non-synonymous mutations in six genes (PIK3CA, FGFR3, TP53, JAK3, MET, FBXW7), and mutations were validated by Sanger sequencing and/or qPCR. Analysis was extended in silico to 530 head and neck (HNSCC) cases using TCGA data. Mutations in PIK3CA and FGFR3 were detected in PD and LSCC cases, as well as other HNSCC cases, but absent in NPD cases. In contrast, mutations in JAK3, MET and FBXW7 were found in NPD cases but not PD, LSCC or other HNSCC cases. TP53 was the most frequently mutated gene in both PD and NPD cases. With the exception of R248W, mutations were mutually exclusive. Moreover, five of seven PD mutations were located in motif H2 of p53, whereas none of the NPD mutations were. In summary, we propose that the mutational profile of laryngeal dysplasia has utility for the early detection of patients at risk of progression.
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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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Coaxum SD, Tiedeken J, Garrett-Mayer E, Myers J, Rosenzweig SA, Neskey DM. The tumor suppressor capability of p53 is dependent on non-muscle myosin IIA function in head and neck cancer. Oncotarget 2017; 8:22991-23007. [PMID: 28160562 PMCID: PMC5410280 DOI: 10.18632/oncotarget.14967] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 01/10/2017] [Indexed: 11/26/2022] Open
Abstract
Over 300,000 patients develop squamous cell carcinoma of the head and neck (HNSCC) worldwide with 25-30% of patients ultimately dying from their disease. Currently, molecular biomarkers are not used in HNSCC but several genes have been identified including mutant TP53 (mutp53) Our recent work has identified an approach to stratify patients with tumors harboring high or low risk TP53 mutations. Non-muscle Myosin IIA (NMIIA) was recently identified as a tumor suppressor in HNSCC. We now demonstrate that low MYH9 expression is associated with decreased survival in patients with head and neck cancer harboring low-risk mutp53 but not high-risk mutp53. Furthermore, inhibition of NMIIA leads to increased invasion in cells harboring wildtype p53 (wtp53), which was not observed in high-risk mutp53 cells. This increased invasiveness of wtp53 following NMIIA inhibition was associated with reduced p53 target gene expression and was absent in cells expressing mutp53. This reduced expression may be due, in part, to a decrease in nuclear localization of wtp53. These findings suggest that the tumor suppressor capability of wtp53 is dependent upon functional NMIIA and that the invasive phenotype of high-risk mutp53 is independent of NMIIA.
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Affiliation(s)
- Sonya D Coaxum
- Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Jessica Tiedeken
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
| | - Elizabeth Garrett-Mayer
- Department of Public Health Sciences and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Jeffrey Myers
- Department of Head & Neck Surgery, M.D. Anderson Medical Center, Houston, TX, USA
| | - Steven A Rosenzweig
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
| | - David M Neskey
- Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA.,Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
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Türke C, Horn S, Petto C, Labudde D, Lauer G, Wittenburg G. Loss of heterozygosity in FANCG, FANCF and BRIP1 from head and neck squamous cell carcinoma of the oral cavity. Int J Oncol 2017; 50:2207-2220. [PMID: 28440438 DOI: 10.3892/ijo.2017.3974] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 02/28/2017] [Indexed: 01/10/2023] Open
Abstract
Recent advances have been made in the understanding of Fanconi anemia (FA), a hereditary disease that increases the risk for head and neck squamous cell carcinomas (HNSCC) by 500- to 700-fold. FA patients harbour germline mutations in genes of cellular DNA repair pathways that are assumed to facilitate the accumulation of mutations during HNSCC development. Mutations in these FA genes may also contribute to HNSCC in general. In the present study, we analysed three FA genes; FANCF, FANCG and BRIP1, that are involved in the repair of DNA inter strand cross-links, in HNSCC and their potential role for patient survival. We measured loss of heterozygosity (LOH) mutations at eight microsatellite loci flanking three FA genes in 54 HNSCC of the oral cavity and corresponding blood samples. Survival analyses were carried out using mutational data and clinical variables. LOH was present in 17% (FANCF region), 41% (FANCG region) and 11% (BRIP1 region) of the patients. Kaplan-Meier survival curves and log-rank tests indicated strong clinical predictors (lymph node stages with decreased survival: p=2.69e-12; surgery with improved survival: p=0.0005). LOH in the FANCF region showed a weaker association with decreased overall survival (p=0.006), which however, did not hold in multivariate analyses. LOH may predominantly indicate copy number gains in FANCF and losses in FANCG and BRIP1. Integration of copy number data and gene expression proved difficult as the available sample sets did not overlap. In conclusion, LOH in FA genes appears to be a common feature of HNSCC development seen here in 57% of patients and other mutation types may increase this mutation frequency. We suggest larger patient cohorts would be needed to test the observed association of LOH in FANCF and patient survival comprehensively.
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Affiliation(s)
- Christin Türke
- Department for Oral and Maxillofacial Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Susanne Horn
- Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, and German Consortium for Translational Cancer Research (DKTK), Essen, Germany
| | - Carola Petto
- Department for Oral and Maxillofacial Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Dirk Labudde
- Department of Bioinformatics, University of Applied Sciences Mittweida, Mittweida, Germany
| | - Günter Lauer
- Department for Oral and Maxillofacial Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Gretel Wittenburg
- Department for Oral and Maxillofacial Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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Tinhofer I, Budach V, Saki M, Konschak R, Niehr F, Jöhrens K, Weichert W, Linge A, Lohaus F, Krause M, Neumann K, Endris V, Sak A, Stuschke M, Balermpas P, Rödel C, Avlar M, Grosu A, Abdollahi A, Debus J, Belka C, Pigorsch S, Combs S, Mönnich D, Zips D, Baumann M. Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation. Eur J Cancer 2016; 57:78-86. [DOI: 10.1016/j.ejca.2016.01.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 01/05/2016] [Accepted: 01/09/2016] [Indexed: 12/22/2022]
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Mori J, Tanikawa C, Funauchi Y, Lo PHY, Nakamura Y, Matsuda K. Cystatin C as a p53-inducible apoptotic mediator that regulates cathepsin L activity. Cancer Sci 2016; 107:298-306. [PMID: 26757339 PMCID: PMC4814261 DOI: 10.1111/cas.12881] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 12/25/2015] [Accepted: 01/03/2016] [Indexed: 01/09/2023] Open
Abstract
In response to various cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes. However, the full picture of the p53 downstream pathway still remains to be elucidated. Here we identified cystatin C, a major inhibitor of cathepsins, as a novel p53 target. In response to DNA damage, activated p53 induced cystatin C expression through p53 binding sequence in the first intron. We showed that cathepsin L activity was decreased in HCT116 p53+/+ cells after adriamycin treatment, but not in HCT116 p53−/− cells. We also found that knockdown of cystatin C reduced adriamycin‐induced caspase‐3 activation. Cystatin C expression was significantly downregulated in breast cancer cells with p53 mutations, and decreased cystatin C expression was associated with poor prognosis of breast cancer. Our findings revealed an important role of the p53–cystatin C pathway in human carcinogenesis.
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Affiliation(s)
- Jinichi Mori
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan
| | - Chizu Tanikawa
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan
| | - Yuki Funauchi
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan
| | - Paulisally Hau Yi Lo
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan
| | - Yusuke Nakamura
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.,Departments of Medicine and Surgery, and Center for Personalized Therapeutics, The University of Chicago, Chicago, Illinois, USA
| | - Koichi Matsuda
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan
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13
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Epstein-Barr virus infection is strictly associated with the metastatic spread of sinonasal squamous-cell carcinomas. Oral Oncol 2015; 51:929-34. [PMID: 26272275 DOI: 10.1016/j.oraloncology.2015.07.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Revised: 07/20/2015] [Accepted: 07/24/2015] [Indexed: 11/22/2022]
Abstract
BACKGROUND Sinonasal squamous-cell carcinomas (SNSCC) are relatively rare. Thus, data regarding the rate of lymph node metastases are inconsistent in contrast with well-known high metastasis rates in squamous-cell carcinomas of the head and neck (HNSCC) (oral cavity, pharynx and larynx). Hence, the indication for elective neck dissection is difficult in SNSCC. The aim of this study was to assess common genetic alterations and EBV and HPV status as a function of metastasis in SNSCC and HNSCC. METHODS We retrospectively analyzed 44 SNSCC and 65 HNSCC for TP53, EGFR, KRAS, PIK3CA and BRAF mutations using a high-resolution melting analysis followed by Sanger sequencing. EBV and HPV detection was performed using in situ hybridization for virus encoded RNA. Tumor-associated p16(INK4a) expression was visualized by immunohistochemistry and correlated with HPV infection. The mutation data, EBV and HPV status were statistically compared with the clinical data in SNSCC and HNSCC. RESULTS TP53 mutations were exclusively associated with shorter survival in SNSCC (p=0.048). All the other markers had no effect on the metastasis rate and survival. In total, 20 of 44 SNSCC were EBV-positive. Only these EBV positive tumors developed lymph node or distant metastases (p=0.008). LMP1 was positive in 14/44 patients. When combining both methods significance for a correlation between EBV/LMP1 positive patients and metastases was even higher (p=0.001). CONCLUSION In SNSCC, the presence of EBV is strictly associated with metastasis. We recommend an elective neck dissection in patients with EBV-positive SNSCC.
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Fitzgerald AL, Osman AA, Xie TX, Patel A, Skinner H, Sandulache V, Myers JN. Reactive oxygen species and p21Waf1/Cip1 are both essential for p53-mediated senescence of head and neck cancer cells. Cell Death Dis 2015; 6:e1678. [PMID: 25766317 PMCID: PMC4385922 DOI: 10.1038/cddis.2015.44] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 12/11/2014] [Accepted: 12/12/2014] [Indexed: 12/15/2022]
Abstract
Treatment of head and neck squamous cell carcinoma, HNSCC, often requires multimodal therapy, including radiation therapy. The efficacy of radiotherapy in controlling locoregional recurrence, the most frequent cause of death from HNSCC, is critically important for patient survival. One potential biomarker to determine radioresistance is TP53 whose alterations are predictive of poor radiation response. DNA-damaging reactive oxygen species (ROS) are a by-product of ionizing radiation that lead to the activation of p53, transcription of p21(cip1/waf1) and, in the case of wild-type TP53 HNSCC cells, cause senescence. The expression of p21 and production of ROS have been associated with the induction of cellular senescence, but the intricate relationship between p21 and ROS and how they work together to induce senescence remains elusive. For the first time, we show that persistent exposure to low levels of the ROS, hydrogen peroxide, leads to the long-term expression of p21 in HNSCC cells with a partially functional TP53, resulting in senescence. We conclude that the level of ROS is crucial in initiating p53's transcription of p21 leading to senescence. It is p21's ability to sustain elevated levels of ROS, in turn, that allows for a long-term oxidative stress, and ensures an active p53-p21-ROS signaling loop. Our data offer a rationale to consider the use of either ROS inducing agents or therapies that increase p21 expression in combination with radiation as approaches in cancer therapy and emphasizes the importance of considering TP53 status when selecting a patient's treatment options.
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Affiliation(s)
- A L Fitzgerald
- Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - A A Osman
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - T-X Xie
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - A Patel
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - H Skinner
- Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - V Sandulache
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX
| | - J N Myers
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
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15
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Osman AA, Neskey DM, Katsonis P, Patel AA, Ward AM, Hsu TK, Hicks SC, McDonald TO, Ow TJ, Alves MO, Pickering CR, Skinner HD, Zhao M, Sturgis EM, Kies MS, El-Naggar A, Perrone F, Licitra L, Bossi P, Kimmel M, Frederick MJ, Lichtarge O, Myers JN. Evolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients. Cancer Res 2015; 75:1205-15. [PMID: 25691460 DOI: 10.1158/0008-5472.can-14-2729] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 01/12/2015] [Indexed: 12/25/2022]
Abstract
TP53 is the most frequently altered gene in head and neck squamous cell carcinoma (HNSCC), with mutations occurring in over two thirds of cases; however, the predictive response of these mutations to cisplatin-based therapy remains elusive. In the current study, we evaluate the ability of the Evolutionary Action score of TP53-coding variants (EAp53) to predict the impact of TP53 mutations on response to chemotherapy. The EAp53 approach clearly identifies a subset of high-risk TP53 mutations associated with decreased sensitivity to cisplatin both in vitro and in vivo in preclinical models of HNSCC. Furthermore, EAp53 can predict response to treatment and, more importantly, a survival benefit for a subset of head and neck cancer patients treated with platinum-based therapy. Prospective evaluation of this novel scoring system should enable more precise treatment selection for patients with HNSCC.
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Affiliation(s)
- Abdullah A Osman
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David M Neskey
- Department of Otolaryngology Head and Neck Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
| | - Panagiotis Katsonis
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas
| | - Ameeta A Patel
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexandra M Ward
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Teng-Kuei Hsu
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas
| | - Stephanie C Hicks
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Thomas J Ow
- Department of Otolaryngology Head and Neck Surgery, Albert Einstein School of Medicine, Bronx, New York
| | - Marcus Ortega Alves
- Department of Internal Medicine, Tufts Medical Center, Boston, Massachusetts
| | - Curtis R Pickering
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Heath D Skinner
- Department of Thoracic Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mei Zhao
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eric M Sturgis
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Merrill S Kies
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Adel El-Naggar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Federica Perrone
- Department of Pathology, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Lisa Licitra
- Head and Neck Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Paolo Bossi
- Head and Neck Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Marek Kimmel
- Department of Statistics, Rice University, Houston, Texas
| | - Mitchell J Frederick
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Olivier Lichtarge
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas
| | - Jeffrey N Myers
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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16
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Neskey DM, Osman AA, Ow TJ, Katsonis P, McDonald T, Hicks SC, Hsu TK, Pickering CR, Ward A, Patel A, Yordy JS, Skinner HD, Giri U, Sano D, Story MD, Beadle BM, El-Naggar AK, Kies MS, William WN, Caulin C, Frederick M, Kimmel M, Myers JN, Lichtarge O. Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer. Cancer Res 2015; 75:1527-36. [PMID: 25634208 DOI: 10.1158/0008-5472.can-14-2735] [Citation(s) in RCA: 120] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 12/02/2014] [Indexed: 01/25/2023]
Abstract
TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations.
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Affiliation(s)
- David M Neskey
- Department of Otolaryngology Head and Neck Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
| | - Abdullah A Osman
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Thomas J Ow
- Department of Otolaryngology Head and Neck Surgery, Albert Einstein School of Medicine, Yeshiva University, New York, New York
| | - Panagiotis Katsonis
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas
| | | | - Stephanie C Hicks
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Teng-Kuei Hsu
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas
| | - Curtis R Pickering
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Alexandra Ward
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Ameeta Patel
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - John S Yordy
- Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas
| | - Heath D Skinner
- Department of Thoracic Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Uma Giri
- Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Daisuke Sano
- Department of Otolaryngology-Head and Neck Surgery, Yokahama University, Yokahama, Japan
| | - Michael D Story
- Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas. Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas
| | - Beth M Beadle
- Department of Head and Neck Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Adel K El-Naggar
- Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Merrill S Kies
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - William N William
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Carlos Caulin
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Mitchell Frederick
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Marek Kimmel
- Department of Statistics, Rice University, Houston, Texas
| | - Jeffrey N Myers
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
| | - Olivier Lichtarge
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas
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17
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Nobusawa A, Sano T, Yokoo S, Oyama T. Ameloblastic carcinoma developing in preexisting ameloblastoma with a mutation of the p53 gene: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 118:e146-50. [DOI: 10.1016/j.oooo.2014.03.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 03/17/2014] [Accepted: 03/30/2014] [Indexed: 10/25/2022]
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18
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Maruyama H, Yasui T, Ishikawa-Fujiwara T, Morii E, Yamamoto Y, Yoshii T, Takenaka Y, Nakahara S, Todo T, Hongyo T, Inohara H. Human papillomavirus and p53 mutations in head and neck squamous cell carcinoma among Japanese population. Cancer Sci 2014; 105:409-17. [PMID: 24521534 PMCID: PMC4317800 DOI: 10.1111/cas.12369] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 01/22/2014] [Accepted: 02/05/2014] [Indexed: 01/29/2023] Open
Abstract
We aimed to reveal the prevalence and pattern of human papillomavirus (HPV) infection and p53 mutations among Japanese head and neck squamous cell carcinoma (HNSCC) patients in relation to clinicopathological parameters. Human papillomavirus DNA and p53 mutations were examined in 493 HNSCCs and its subset of 283 HNSCCs. Oropharyngeal carcinoma was more frequently HPV-positive than non-oropharyngeal carcinoma (34.4% vs 3.6%, P < 0.001), and HPV16 accounted for 91.1% of HPV-positive tumors. In oropharyngeal carcinoma, which showed an increasing trend of HPV prevalence over time (P < 0.001), HPV infection was inversely correlated with tobacco smoking, alcohol drinking, p53 mutations, and a disruptive mutation (P = 0.003, <0.001, <0.001, and <0.001, respectively). The prevalence of p53 mutations differed significantly between virus-unrelated HNSCC and virus-related HNSCC consisting of nasopharyngeal and HPV-positive oropharyngeal carcinomas (48.3% vs 7.1%, P < 0.001). Although p53 mutations were associated with tobacco smoking and alcohol drinking, this association disappeared in virus-unrelated HNSCC. A disruptive mutation was never found in virus-related HNSCC, whereas it was independently associated with primary site, such as the oropharynx and hypopharynx (P = 0.01 and 0.03, respectively), in virus-unrelated HNSCC. Moreover, in virus-unrelated HNSCC, G:C to T:A transversions were more frequent in ever-smokers than in never-smokers (P = 0.04), whereas G:C to A:T transitions at CpG sites were less frequent in ever-smokers than in never-smokers (P = 0.04). In conclusion, HNSCC is etiologically classified into virus-related and virus-unrelated subgroups. In virus-related HNSCC, p53 mutations are uncommon with the absence of a disruptive mutation, whereas in virus-unrelated HNSCC, p53 mutations are common, and disruptive mutagenesis of p53 is related with oropharyngeal and hypopharyngeal carcinoma.
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Affiliation(s)
- Hiromi Maruyama
- Department of Otorhinolaryngology - Head and Neck Surgery, Osaka University Faculty of Medicine, Suita, Japan
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19
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Ganci F, Sacconi A, Bossel Ben-Moshe N, Manciocco V, Sperduti I, Strigari L, Covello R, Benevolo M, Pescarmona E, Domany E, Muti P, Strano S, Spriano G, Fontemaggi G, Blandino G. Expression of TP53 mutation-associated microRNAs predicts clinical outcome in head and neck squamous cell carcinoma patients. Ann Oncol 2013; 24:3082-8. [PMID: 24107801 DOI: 10.1093/annonc/mdt380] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND TP53 mutation is associated with decreased survival rate in head and neck squamous cell carcinoma (HNSCC) patients. We set out to identify microRNAs (miRNAs) whose expression associates with TP53 mutation and survival in HNSCC. PATIENTS AND METHODS We analyzed TP53 status by direct sequencing of exons 2 through 11 of a prospective series of 121 HNSCC samples and assessed its association with outcome in 109 followed-up patients. We carried out miRNA expression profiling on 121 HNSCC samples and 66 normal counterparts. miRNA associations with TP53 mutations and outcome were evaluated. RESULTS A TP53 mutation was present in 58% of the tumors and TP53 mutations were significantly associated with a shorter recurrence-free survival. This association was stronger in the clinical subgroup of patients subjected to adjuvant therapy after surgery. The expression of 49 miRNAs was significantly associated with TP53 status. Among these 49, we identified a group of 12 miRNAs whose expression correlates with recurrence-free survival and a group of 4 miRNAs that correlates with cancer-specific survival. The two groups share three miRNAs. Importantly, miRNAs that correlate with survival are independent prognostic factors either when considered individually or as signatures. CONCLUSIONS miRNAs expression associates with TP53 status and with reduced survival after surgical treatment of squamous cell carcinoma of the head and neck.
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Affiliation(s)
- F Ganci
- Translational Oncogenomics Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy
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20
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Anderson RT, Keysar SB, Bowles DW, Glogowska MJ, Astling DP, Morton JJ, Le P, Umpierrez A, Eagles-Soukup J, Gan GN, Vogler BW, Sehrt D, Takimoto SM, Aisner DL, Wilhelm F, Frederick BA, Varella-Garcia M, Tan AC, Jimeno A. The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas. Mol Cancer Ther 2013; 12:1994-2005. [PMID: 23873848 PMCID: PMC3796006 DOI: 10.1158/1535-7163.mct-13-0206] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in squamous cell carcinoma of the head and neck (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from eight patients with HNSCC [four HPV-serotype16 (HPV16)-positive]. HNSCC cell lines and xenografts were characterized by pathway enrichment gene expression analysis, exon sequencing, gene copy number, Western blotting, and immunohistochemistry (IHC). Rigosertib had potent antiproliferative effects on 11 of 16 HPV(-) HNSCC cell lines. Treatment sensitivity was confirmed in two cell lines using an orthotopic in vivo xenograft model. Growth reduction after rigosertib treatment was observed in three of eight HNSCC direct patient tumor lines. The responsive tumor lines carried a combination of a PI3KCA-activating event (amplification or mutation) and a p53-inactivating event (either HPV16- or mutation-mediated TP53 inactivation). In this study, we evaluated the in vitro and in vivo efficacy of rigosertib in both HPV(+) and HPV(-) HNSCCs, focusing on inhibition of the PI3K pathway. Although consistent inhibition of the PI3K pathway was not evident in HNSCC, we identified a combination of PI3K/TP53 events necessary, but not sufficient, for rigosertib sensitivity.
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Affiliation(s)
- Ryan T Anderson
- Corresponding Author: Antonio Jimeno, University of Colorado School of Medicine, MS8117, 12801 East 17th Avenue, Room L18-8101B, Aurora, CO 80045.
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21
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Habl G, Potthoff K, Haefner MF, Abdollahi A, Hassel JC, Boller E, Indorf M, Debus J. Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (head and neck cancer: immunochemo and radiotherapy with erbitux) - a multicenter phase IV trial. BMC Cancer 2013; 13:345. [PMID: 23855804 PMCID: PMC3751099 DOI: 10.1186/1471-2407-13-345] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2012] [Accepted: 07/10/2013] [Indexed: 11/23/2022] Open
Abstract
Background In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before. Methods/design The HICARE study is a national, multicenter, prospective phase IV study exploring the different types of skin reactions that occur in patients with LASCCHN undergoing radioimmun(chemo)therapy with the EGFR inhibitor cetuximab. 500 patients with LASCCHN will be enrolled in 40 participating sites in Germany. Primary endpoint is the rate of radiation dermatitis NCI CTCAE grade 3 and 4 (v. 4.02). Radioimmunotherapy will be applied according to SmPC, i.e. cetuximab will be administered as loading dose and then weekly during the radiotherapy. Irradiation will be applied as intensity-modulated radiation therapy (IMRT) or 3D-dimensional radiation therapy. Discussion The HICARE trial is expected to be one of the largest trials ever conducted in head and neck cancer patients. The goal of the HICARE trial is to differentiate skin reactions caused by radiation from those caused by the monoclonal antibody cetuximab, to evaluate the incidence and severity of these skin reactions and to correlate them with outcome parameters. Besides, the translational research program will help to identify and confirm novel peripheral blood based molecular predictors and surrogates for treatment response and resistance. Trial registration Clinical Trial Identifier, NCT01553032 (clinicaltrials.gov) EudraCT number: 2010-019748-38
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Affiliation(s)
- G Habl
- Department of Radiation Oncology, University of Heidelberg Medical Center, Im Neuenheimer Feld 400, Heidelberg, 69120, Germany.
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Hoffmann TK. Systemic therapy strategies for head-neck carcinomas: Current status. GMS CURRENT TOPICS IN OTORHINOLARYNGOLOGY, HEAD AND NECK SURGERY 2012; 11:Doc03. [PMID: 23320055 PMCID: PMC3544206 DOI: 10.3205/cto000085] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Head and neck cancers, most of which are squamous cell tumours, have an unsatisfactory prognosis despite intensive local treatment. This can be attributed, among other factors, to tumour recurrences inside or outside the treated area, and metastases at more distal locations. These tumours therefore require not only the standard surgical and radiation treatments, but also effective systemic modalities. The main option here is antineoplastic chemotherapy, which is firmly established in the palliative treatment of recurrent or metastatic stages of disease, and is used with curative intent in the form of combined simultaneous or adjuvant chemoradiotherapy in patients with inoperable or advanced tumour stages. Neoadjuvant treatment strategies for tumour reduction before surgery have yet to gain acceptance. Induction chemotherapy protocols before radiotherapy have to date been used in patients at high risk of distant metastases or as an aid for decision-making ("chemoselection") in those with extensive laryngeal cancers, prior to definitive chemoradiotherapy or laryngectomy. Triple-combination induction therapy (taxanes, cisplatin, 5-fluorouracil) shows high remission rates with significant toxicity and, in combination with (chemo-)radiotherapy, is currently being compared with simultaneous chemoradiotherapy; the current gold standard with regards to efficacy and long-term toxicity.A further systemic treatment strategy, called "targeted therapy", has been developed to help increase specificity and reduce toxicity. An example of targeted therapy, EGFR-specific antibodies, can be used in palliative settings and, in combination with radiotherapy, to treat advanced head and neck cancers. A series of other novel biologicals such as signal cascade inhibitors, genetic agents, or immunotherapies, are currently being evaluated in large-scale clinical studies, and could prove useful in patients with advanced, recurring or metastatic head and neck cancers. When developing a lasting, individualised systemic tumour therapy, the critical evaluation criteria are not only efficacy and acute toxicity but also (long-term) quality-of-life and the identification of dedicated predictive biomarkers.
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Inoue K, Kurabayashi A, Shuin T, Ohtsuki Y, Furihata M. Overexpression of p53 protein in human tumors. Med Mol Morphol 2012; 45:115-23. [PMID: 23001293 DOI: 10.1007/s00795-012-0575-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Accepted: 02/14/2012] [Indexed: 01/30/2023]
Abstract
According to the current concept of carcinogenesis, neoplastic transformation consists of multistep accumulations of adverse genetic and epigenetic events. p53 is a transcription factor that regulates cellular response to diverse forms of stress through a complex network which monitors genome integrity and cell homeostasis. Mutant p53 loss-of-function, dominant-negative, and gain-of-function properties have been implicated in the development of a wide variety of human cancers, and it is generally accepted that p53 is a component in biochemical pathways central to human carcinogenesis. Study of p53 has come to the forefront of cancer research, and detection of its abnormalities during the development of tumors may have diagnostic, prognostic, and therapeutic implications. In this review, we focus on recent research on overexpression of mutant p53 in human cancer, with an emphasis on mutant p53 regulation, gain of function of mutant p53 in transcriptional effects, and the diagnostic, prognostic, and predictive value of p53 overexpression in human cancer.
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Affiliation(s)
- Keiji Inoue
- Department of Urology, Kochi Medical School, Nankoku, Kochi, Japan.
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Loyo M, Li RJ, Bettegowda C, Pickering CR, Frederick MJ, Myers JN, Agrawal N. Lessons learned from next-generation sequencing in head and neck cancer. Head Neck 2012; 35:454-63. [PMID: 22907887 DOI: 10.1002/hed.23100] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2012] [Indexed: 12/30/2022] Open
Abstract
Scientific innovation has enabled whole exome capture and massively parallel sequencing of cancer genomes. In head and neck cancer, next-generation sequencing has granted us further understanding of the mutational spectrum of squamous cell carcinoma. As a result of these new technologies, frequently occurring mutations were identified in NOTCH1, a gene that had not previously been implicated in head and neck cancer. The current review describes the most common mutations in head and neck cancer: TP53, NOTCH1, HRAS, PIK3CA, and CDKN2A. Emphasis is placed on the involved cellular pathways, clinical correlations, and potential therapeutic interventions. Additionally, the implications of human papillomavirus on mutation patterns are discussed.
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Affiliation(s)
- Myriam Loyo
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Park BJ, Chiosea SI, Grandis JR. Molecular changes in the multistage pathogenesis of head and neck cancer. Cancer Biomark 2012; 9:325-39. [PMID: 22112483 DOI: 10.3233/cbm-2011-0163] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Head and neck squamous cell carcinomas (SCCHN) arise in the mucosa of the upper aerodigestive tract at multiple anatomic sites. While tobacco and alcohol exposure remain the primary risk factors for this malignancy, infection with the human papilloma virus is emerging as a major contributing factor to cancers that arise primarily in the oropharynx. Despite therapeutic advances, survival has remained relatively unchanged over the past few decades. Increased understand of the cellular and molecular biology of these cancers will improve our understanding of this malignancy and facilitate the development of more effective therapeutic strategies. Alterations that have been studied to date include genetic and epigenetic changes. While the epidermal growth factor receptor (EGFR) is the only established molecular therapeutic target, other proteins and pathways are under active investigation to determine their contribution to SCCHN carcinogenesis and progression.
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Affiliation(s)
- Brian J Park
- Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA
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Van der Vorst S, Dekairelle AF, Weynand B, Hamoir M, Gala JL. Assessment of p53 functional activity in tumor cells and histologically normal mucosa from patients with head and neck squamous cell carcinoma. Head Neck 2011; 34:1542-50. [PMID: 22109999 DOI: 10.1002/hed.21960] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Revised: 08/04/2011] [Accepted: 09/06/2011] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The purpose of this study was to investigate the value of p53 functional analysis of separated alleles in yeast (FASAY) as a witness of p53/p21 pathway alteration in head and neck squamous cell carcinoma (HNSCC). METHODS The p53 transcriptional activity was prospectively analyzed in 82 newly diagnosed patients with HNSCC. FASAY and p53 immunostaining were carried out on paired tumoral and histologically normal tissues. The predictive value of FASAY for locoregional recurrence was assessed by Cox survival analysis. RESULTS Loss of p53/p21 transcriptional activity was encountered in 88% tumoral and 18% histologically normal samples, associated with mutations (79%) and insertions/deletions (21%). The p53 overexpression underestimated p53 transcriptional abnormalities. FASAY-positive histologically normal mucosa was significantly associated with locoregional recurrence. CONCLUSION FASAY positivity indicates field cancerization in a subgroup of patients with HNSCC, in which nonfunctional p53 was significantly associated with locoregional recurrence. This prompted us to pursue the study on the p53 functional status of normal mucosa in patients with HNSCC.
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Affiliation(s)
- Sébastien Van der Vorst
- Center for Applied Molecular Technologies, Institute for Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
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Skinner HD, Sandulache VC, Ow TJ, Meyn RE, Yordy JS, Beadle BM, Fitzgerald AL, Giri U, Ang KK, Myers JN. TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence. Clin Cancer Res 2011; 18:290-300. [PMID: 22090360 DOI: 10.1158/1078-0432.ccr-11-2260] [Citation(s) in RCA: 224] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE Mortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity. EXPERIMENTAL DESIGN Seventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell lines were assembled; for each, TP53 was sequenced and the in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using short hairpin RNA (shRNA) and overexpressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and reactive oxygen species (ROS) assays were carried out. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model. RESULTS Mutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (P = 0.03). Cell lines with disruptive mutations were significantly more radioresistant (P < 0.05). Expression of disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA-β-gal staining, p21 expression, and release of ROS. The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin. CONCLUSIONS Disruptive TP53 mutations in HNSCC tumors predicts for LRR, because of increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment.
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Affiliation(s)
- Heath D Skinner
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Chen GX, Zheng LH, Liu SY, He XH. rAd-p53 enhances the sensitivity of human gastric cancer cells to chemotherapy. World J Gastroenterol 2011; 17:4289-97. [PMID: 22090785 PMCID: PMC3214704 DOI: 10.3748/wjg.v17.i38.4289] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2010] [Revised: 04/19/2011] [Accepted: 04/26/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate potential antitumor effects of rAd-p53 by determining if it enhanced sensitivity of gastric cancer cells to chemotherapy.
METHODS: Three gastric cancer cell lines with distinct levels of differentiation were treated with various doses of rAd-p53 alone, oxaliplatin (OXA) alone, or a combination of both. Cell growth was assessed with an 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-diphenytetrazoliumromide assay and the expression levels of p53, Bax and Bcl-2 were determined by immunohistochemistry. The presence of apoptosis and the expression of caspase-3 were determined using flow cytometry.
RESULTS: Treatment with rAd-p53 or OXA alone inhibited gastric cancer cell growth in a time- and dose-dependent manner; moreover, significant synergistic effects were observed when these treatments were combined. Immunohistochemical analysis demonstrated that treatment with rAd-p53 alone, OXA alone or combined treatment led to decreased Bcl-2 expression and increased Bax expression in gastric cancer cells. Furthermore, flow cytometry showed that rAd-p53 alone, OXA alone or combination treatment induced apoptosis of gastric cancer cells, which was accompanied by increased expression of caspase-3.
CONCLUSION: rAd-p53 enhances the sensitivity of gastric cancer cells to chemotherapy by promoting apoptosis. Thus, our results suggest that p53 gene therapy combined with chemotherapy represents a novel avenue for gastric cancer treatment.
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Lee J, Moon C. Current status of experimental therapeutics for head and neck cancer. Exp Biol Med (Maywood) 2011; 236:375-89. [PMID: 21427235 DOI: 10.1258/ebm.2010.010354] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
As with many cancers, early detection of head and neck cancer increases a patient's survival rate. If diagnosed early, its five-year survival nears 90% with standard therapy alone. Unfortunately, the average survival rate for head and neck cancer is low due to the difficulty in early detection and achieving a sustainable response. Conventional treatments are not adequate for the majority of advanced or recurrent head and neck cancer patients because of the remarkable resistance of tumors to chemotherapy and radiation, and the situation is especially devastating for the first time treatment failure. The major limitations of these treatments are the lack of specificity for the tumor cell and unacceptable toxicity to the patient. As a result, current research in therapeutics for advanced, chemotherapy-resistant or recurrent head and neck cancer patients has focused on new treatment modalities that exploit biological differences between tumor and normal cells. These therapies include monoclonal antibodies, molecular inhibitors, gene therapy and photodynamic therapy. This article reviews the current preclinical and clinical evidence of these experimental therapeutics as they relate to head and neck cancer.
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Affiliation(s)
- Juna Lee
- Graduate Program in Human Genetics, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21218, USA
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Pandith AA, Shah ZA, Khan NP, Rasool R, Afroze D, Yousuf A, Wani S, Siddiqi M. Role of TP53 Arg72Pro polymorphism in urinary bladder cancer predisposition and predictive impact of proline related genotype in advanced tumors in an ethnic Kashmiri population. ACTA ACUST UNITED AC 2010; 203:263-8. [DOI: 10.1016/j.cancergencyto.2010.08.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2010] [Revised: 07/07/2010] [Accepted: 08/08/2010] [Indexed: 11/26/2022]
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Prince A, Aguirre-Ghizo J, Genden E, Posner M, Sikora A. Head and Neck Squamous Cell Carcinoma: New Translational Therapies. ACTA ACUST UNITED AC 2010; 77:684-99. [PMID: 21105129 DOI: 10.1002/msj.20216] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Robles AI, Harris CC. Clinical outcomes and correlates of TP53 mutations and cancer. Cold Spring Harb Perspect Biol 2010; 2:a001016. [PMID: 20300207 DOI: 10.1101/cshperspect.a001016] [Citation(s) in RCA: 216] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The initial observation that p53 accumulation might serve as a surrogate biomarker for TP53 mutation has been the cornerstone for vast translational efforts aimed at validating its clinical use for the diagnosis, prognosis, and treatment of cancer. Early on, it was realized that accurate evaluation of p53 status and function could not be achieved through protein-expression analysis only. As our understanding of the p53 pathway has evolved and more sophisticated methods for assessment of p53 functional integrity have become available, the clinical and molecular epidemiological implications of p53 abnormalities in cancers are being revealed. They include diagnostic testing for germline p53 mutations, and the assessment of selected p53 mutations as biomarkers of carcinogen exposure and cancer risk and prognosis. Here, we describe the strengths and limitations of the most frequently used techniques for determination of p53 status in tumors, as well as the most remarkable latest findings relating to its clinical and epidemiological value.
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Affiliation(s)
- Ana I Robles
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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Perrone F, Bossi P, Cortelazzi B, Locati L, Quattrone P, Pierotti MA, Pilotti S, Licitra L. TP53 Mutations and Pathologic Complete Response to Neoadjuvant Cisplatin and Fluorouracil Chemotherapy in Resected Oral Cavity Squamous Cell Carcinoma. J Clin Oncol 2010; 28:761-6. [DOI: 10.1200/jco.2009.22.4170] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose To find out if TP53 functional status predicts response to neoadjuvant chemotherapy and thus may be helpful during treatment decision making of oral cavity squamous cell carcinoma (SCC) patients. Patients and Methods We analyzed the predictive value of TP53 mutations and their functional status on the basis of the transactivation activity of p53 mutant proteins in 53 pretreatment biopsies of oral cavity SCC patients receiving primary cisplatin and fluorouracil chemotherapy followed by surgery. Results The surgical specimens showed that 15 patients (28%) achieved a pathologic complete remission (pCR) at both T and N sites, and 38 patients had residual tumor cells. Among the 53 pretreatment biopsies, 24 (45%) displayed TP53 mutations: 22 single-nucleotide substitutions and two deletions. According to functional status that could be determined only for the 22 substitutions, 21 mutations were nonfunctional and one was partially functional. TP53 mutation was found in four (27%) of 15 patients who achieved a pCR and in 20 (53%) of 38 nonresponder patients; the difference was not statistically significant (P = .12). In contrast, two (14%) of 14 cases with pCR carried a nonfunctional TP53 mutation, a frequency significantly less than that found in the nonresponders (19 [51%] of 37; P = .02). TP53 mutation predicted pCR in four (17%) of 24 patients and a nonfunctional mutation in only two (9%) of 22 patients. Conclusion The results indicate that the loss of function (transactivation activities) of p53 mutant proteins may predict a significant low pCR rate and suboptimal response to cisplatin-based neoadjuvant chemotherapy in patients with oral cavity SCC.
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Affiliation(s)
- Federica Perrone
- From the Unit of Experimental Molecular Pathology, Department of Pathology, and the Head and Neck Cancer Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Paolo Bossi
- From the Unit of Experimental Molecular Pathology, Department of Pathology, and the Head and Neck Cancer Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Barbara Cortelazzi
- From the Unit of Experimental Molecular Pathology, Department of Pathology, and the Head and Neck Cancer Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Laura Locati
- From the Unit of Experimental Molecular Pathology, Department of Pathology, and the Head and Neck Cancer Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Pasquale Quattrone
- From the Unit of Experimental Molecular Pathology, Department of Pathology, and the Head and Neck Cancer Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Marco A. Pierotti
- From the Unit of Experimental Molecular Pathology, Department of Pathology, and the Head and Neck Cancer Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Silvana Pilotti
- From the Unit of Experimental Molecular Pathology, Department of Pathology, and the Head and Neck Cancer Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Lisa Licitra
- From the Unit of Experimental Molecular Pathology, Department of Pathology, and the Head and Neck Cancer Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
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Mroz EA, Rocco JW. Functional p53 status as a biomarker for chemotherapy response in oral-cavity cancer. J Clin Oncol 2010; 28:715-7. [PMID: 20048171 DOI: 10.1200/jco.2009.26.3475] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Sahoo R, Chittibabu V, Patil G, Rao S, Thakur S, Dhondalay G, Kulkarni A, Banerjee A, Ajaikumar B, Korlimarla A, Nargund A, Niti R, Gopinath K, Prabhudesai S, Raghavendra R. Relationship between molecular markers and treatment response in a retrospective cohort of Indian patients with primary carcinoma of the larynx. Oral Oncol 2009; 45:e216-21. [DOI: 10.1016/j.oraloncology.2009.07.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2009] [Revised: 07/16/2009] [Accepted: 07/16/2009] [Indexed: 02/01/2023]
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Katkoori VR, Jia X, Shanmugam C, Wan W, Meleth S, Bumpers H, Grizzle WE, Manne U. Prognostic significance of p53 codon 72 polymorphism differs with race in colorectal adenocarcinoma. Clin Cancer Res 2009; 15:2406-16. [PMID: 19339276 DOI: 10.1158/1078-0432.ccr-08-1719] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE Several studies have examined the prognostic value of the codon 72 polymorphism of the p53 gene in colorectal adenocarcinoma, but none have addressed patient race/ethnicity. Therefore, this study assessed the prognostic value of this polymorphism in African American and Caucasian colorectal adenocarcinoma patients separately. EXPERIMENTAL DESIGN Colorectal adenocarcinomas from 137 African Americans and 236 non-Hispanic Caucasians were assessed for p53 mutations and genotyped for the codon 72 polymorphism. The phenotypes were correlated with p53 mutational status, clinicopathologic features, and patient survival using the chi(2) test and Kaplan-Meier and Cox regression models. RESULTS The incidence of p53 mutations was similar in African American and Caucasian patients (50% versus 54%, respectively); however, the homozygous Pro72 allele frequency was higher in African Americans (17%) as compared with Caucasians (7%). In contrast, the homozygous Arg72 allele frequency was higher in Caucasians (36%) than in African Americans (19%). In African Americans but not Caucasians, the Pro/Pro phenotype significantly correlated with a higher incidence of missense p53 mutations and with nodal metastasis. African Americans, but not Caucasians, with the Pro/Pro phenotype had significantly higher mortality (log-rank P = 0.005 versus. P = 0.886) and risk of death due to colorectal adenocarcinoma (hazard ratio, 2.15; 95% confidence interval, 1.02-4.53 versus hazard ratio, 1.60; 95% confidence interval, 0.69-3.18) than those with the phenotype Arg/Arg or Arg/Pro. CONCLUSIONS The higher frequency of the Pro/Pro phenotype of p53 in African American patients with colorectal adenocarcinoma is associated with an increased incidence of p53 mutations, with advanced tumor stage, and with short survival.
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Affiliation(s)
- Venkat R Katkoori
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-7331, USA
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Solcia E, Klersy C, Mastracci L, Alberizzi P, Candusso ME, Diegoli M, Tava F, Riboni R, Manca R, Luinetti O. A combined histologic and molecular approach identifies three groups of gastric cancer with different prognosis. Virchows Arch 2009; 455:197-211. [PMID: 19672623 DOI: 10.1007/s00428-009-0813-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2009] [Revised: 07/06/2009] [Accepted: 07/15/2009] [Indexed: 12/22/2022]
Abstract
The limited prognostic value of currently used histologic classifications of gastric cancer and their failure to account for the complexity of the disease as revealed by more recent investigations prompted a combined reinvestigation of histologic, molecular, and clinicopathologic patterns in 294 extensively sampled, invasive gastric cancers representing all main histotypes and stages of the disease and followed for a median of 150 months. Among histologic parameters tested, only cellular atypia, angio-lympho- or neuroinvasion, Ki67 proliferation index, expansile/infiltrative type growth, and T8 cell-rich high lymphoid intra-/peritumor response (HLR) proved to be stage-independent predictors of patient survival. Among molecular tests, p53 gene exon 7 (loop 3) and 8 (loop-sheet-helix motif and S-10 band), but not p53 protein overexpression, TP53 LOH or 18qLOH, were found to worsen prognosis. Microsatellite DNA instability was a favorable prognostic factor when coupled with HLR. Patient survival analysis of the main histotypes and their subtypes confirmed the favorable prognosis of HLR, well-differentiated tubular, muconodular, and low grade diffuse desmoplastic cancers, and highlighted the worse prognosis of anaplastic and infiltrative-lymphoinvasive mucinous cancers compared to ordinary cohesive and diffuse cancers. Distinct roles of individual morphologic and molecular factors in tumor progression of the different histotypes have been recognized. The combination of survival-predictive histotypes and individual histologic or molecular parameters allowed us to develop a classification of all gastric cancers into three grades of increasing malignancy which proved to be of high prognostic value.
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Affiliation(s)
- Enrico Solcia
- Anatomic Pathology Service, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.
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Toffoli G, Biason P, Russo A, De Mattia E, Cecchin E, Hattinger CM, Pasello M, Alberghini M, Ferrari C, Scotlandi K, Picci P, Serra M. Effect of TP53 Arg72Pro and MDM2 SNP309 polymorphisms on the risk of high-grade osteosarcoma development and survival. Clin Cancer Res 2009; 15:3550-6. [PMID: 19451596 DOI: 10.1158/1078-0432.ccr-08-2249] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The germ-line polymorphisms TP53 Arg72Pro and MDM2 SNP309 T>G are risk factors for tumor development and affect response to chemotherapy and survival in several cancers, but their prognostic and predictive value in patients with high-grade osteosarcomas is not yet defined. The purpose of this study was to investigate the effect of the TP53 Arg72Pro and the MDM2 SNP309 on the risk of osteosarcoma development and survival. EXPERIMENTAL DESIGN The relative risk to develop osteosarcomas and the overall survival associated to TP53 Arg72Pro and MDM2 SNP309 polymorphisms were investigated in 201 patients. Correlations with event-free survival (EFS) were analyzed in a homogeneous subgroup of 130 patients with high-grade osteosarcomas of the limbs, nonmetastatic at diagnosis, which underwent neoadjuvant chemotherapy. RESULTS Multivariate analysis showed that the MDM2 polymorphism T309G was associated with an increased risk of developing osteosarcomas [GG versus TT; odds ratio, 2.09; 95% confidence interval (95% CI), 1.15-3.78]. A case/control gender approach evidenced a significant increased risk only for female osteosarcoma patients (GG versus TT; odds ratio, 4.26; 95% CI, 1.61-11.25). Subjects carrying the TP53 Arg72Pro polymorphism were found to have a significantly increased death risk (Pro/Pro versus Arg/Arg; hazard ratio, 2.90; 95% CI, 1.28-6.66). In the subgroup of 130 high-grade osteosarcomas, the TP53 Arg72Pro was an independent marker of EFS (Pro/Pro versus Arg/Arg; hazard ratio, 2.67; 95% CI, 1.17-6.11). CONCLUSION The study provides evidence supporting the association of MDM2 SNP309 with high-grade osteosarcoma risk in females and shows that TP53 Arg72Pro has a prognostic value for overall survival and EFS in osteosarcoma patients.
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Affiliation(s)
- Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico-National Cancer Institute, Aviano, Italy.
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Pai SI, Westra WH. Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment. ANNUAL REVIEW OF PATHOLOGY 2009; 4:49-70. [PMID: 18729723 PMCID: PMC3703474 DOI: 10.1146/annurev.pathol.4.110807.092158] [Citation(s) in RCA: 332] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The prototypic head and neck squamous cell carcinoma (HNSCC) arises from the mucosal lining of the upper aerodigestive tract, demonstrates squamous differentiation microscopically, involves older men with a long history of cigarette smoking and alcohol consumption, and is treated by multimodality therapy. HNSCC has long been regarded as a uniform disease process requiring a methodical and unwavering therapeutic approach. Divergence in epidemiologic trends among HNSCCs arising from different anatomic sites has introduced a view that, morphologic repetition aside, head and neck cancers form a heterogeneous group. This view has been supported at the molecular genetic level. A more complete understanding of the molecular genetics of head and neck cancer is providing new insights into long-held but poorly comprehended concepts such as field cancerization and is introducing various biomarkers with potential application for diagnosing, staging, monitoring, and prognosticating HNSCC.
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Affiliation(s)
- Sara I. Pai
- Department of Otolarygology, Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231
| | - William H. Westra
- Department of Otolarygology, Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231
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Borkosky SS, Gunduz M, Nagatsuka H, Beder LB, Gunduz E, Ali MALS, Rodriguez AP, Cilek MZ, Tominaga S, Yamanaka N, Shimizu K, Nagai N. Frequent deletion of ING2 locus at 4q35.1 associates with advanced tumor stage in head and neck squamous cell carcinoma. J Cancer Res Clin Oncol 2008; 135:703-13. [PMID: 18998165 DOI: 10.1007/s00432-008-0507-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2008] [Accepted: 10/20/2008] [Indexed: 10/21/2022]
Abstract
BACKGROUND Loss of heterozygosity (LOH) in the ING family members has been shown in head and neck squamous cell carcinoma (HNSCC) except for ING2. Like all the other members of ING family, ING2, which is located at chromosome 4q35.1, is a promising tumor suppressor gene (TSG). In this study, we performed LOH analysis of ING2 in HNSCC and compared it with clinicopathological variables. MATERIALS AND METHODS We performed LOH analysis in DNAs from 80 paired of normal and HNSCC tissues, using a specifically designed microsatellite marker on chromosome 4q35.1, which detects allelic loss of ING2. TP53 mutation analysis and its relationship with ING2 chromosomal deletion were also performed in available 68 of the samples. The correlation between LOH status and clinicopathological characteristics was evaluated by using statistical methods. The overall survival (OS) and disease free survival (DFS) were also determined. RESULTS LOH was detected in 54.6% (30/55) of the informative samples. Statistical significance was obtained between LOH and tumor (T) stage (P = 0.02), application of radiotherapy and chemotherapy. Positive node status (N) appeared to be the only independent prognostic factor for both OS (P = 0.031) and DFS (P = 0.044). CONCLUSIONS Our study showed allelic loss of 4q35.1 in HNSCC. The high percentage of LOH suggests ING2 as a candidate TSG in HNSCC. High LOH frequency was statistically associated with advanced T stage, suggesting that ING2 LOH might occur in late stages during HNSCC progression.
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Affiliation(s)
- Silvia S Borkosky
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Okayama, Japan
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Young KH, Leroy K, Møller MB, Colleoni GWB, Sánchez-Beato M, Kerbauy FR, Haioun C, Eickhoff JC, Young AH, Gaulard P, Piris MA, Oberley TD, Rehrauer WM, Kahl BS, Malter JS, Campo E, Delabie J, Gascoyne RD, Rosenwald A, Rimsza L, Huang J, Braziel RM, Jaffe ES, Wilson WH, Staudt LM, Vose JM, Chan WC, Weisenburger DD, Greiner TC. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood 2008; 112:3088-3098. [PMID: 18559976 PMCID: PMC2569165 DOI: 10.1182/blood-2008-01-129783] [Citation(s) in RCA: 142] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2008] [Accepted: 06/02/2008] [Indexed: 12/14/2022] Open
Abstract
The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell-like DLBCL, but not nongerminal center B cell-like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.
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Affiliation(s)
- Ken H Young
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, USA.
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43
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Koehn J, Krapfenbauer K, Huber S, Stein E, Sutter W, Watzinger F, Erovic BM, Thurnher D, Schindler T, Fountoulakis M, Turhani D. Potential Involvement of MYC- and p53-Related Pathways in Tumorigenesis in Human Oral Squamous Cell Carcinoma Revealed by Proteomic Analysis. J Proteome Res 2008; 7:3818-29. [DOI: 10.1021/pr800077a] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Jadranka Koehn
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
| | - Kurt Krapfenbauer
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
| | - Susanna Huber
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
| | - Elisabeth Stein
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
| | - Walter Sutter
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
| | - Franz Watzinger
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
| | - Boban M. Erovic
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
| | - Dietmar Thurnher
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
| | - Thomas Schindler
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
| | - Michael Fountoulakis
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
| | - Dritan Turhani
- Department of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria, Novartis Institutes for Biomedical Research, Novartis, Vienna, Austria, Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria, and Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland
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Kumar B, Cordell KG, Lee JS, Worden FP, Prince ME, Tran HH, Wolf GT, Urba SG, Chepeha DB, Teknos TN, Eisbruch A, Tsien CI, Taylor JMG, D'Silva NJ, Yang K, Kurnit DM, Bauer JA, Bradford CR, Carey TE. EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 2008; 26:3128-37. [PMID: 18474878 PMCID: PMC2744895 DOI: 10.1200/jco.2007.12.7662] [Citation(s) in RCA: 476] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To prospectively identify markers of response to therapy and outcome in an organ-sparing trial for advanced oropharyngeal cancer. PATIENTS AND METHODS Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status. RESULTS EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and disease-specific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = .009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS (rho(EGFR) = 0.008; rho(HPV) = 0.03) and DSS (rho(EGFR) = 0.01; rho(HPV) = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = .005) and DSS (P = .002). CONCLUSION Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.
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Affiliation(s)
- Bhavna Kumar
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan Comprehensive Cancer Center Head and Neck Cancer Program, Ann Arbor, MI 48109, USA
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Abstract
Despite advances in understanding the underlying genetics, squamous cell carcinoma of the head and neck (SCCHN) remains a major health risk and one of the leading causes of mortality in the world. Current standards of treatment have significantly improved long-term survival rates of patients, but second tumors and metastases still remain the most frequent cause of high mortality in SCCHN patients. A better understanding of the underlying genetic mechanisms of SCCHN tumorigenesis will help in developing better diagnostics and, hence, better cures. In this article we will briefly outline the current state of diagnostics and treatment and our understanding of the molecular causes of SCCHN.
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Affiliation(s)
- Amit M Deshpande
- School of Dentistry and Dental Research Institute, University of California Los Angeles, CA, USA.
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Kumar B, Cordell KG, D’Silva N, Prince ME, Adams ME, Fisher SG, Wolf GT, Carey TE, Bradford CR. Expression of p53 and Bcl-xL as predictive markers for larynx preservation in advanced laryngeal cancer. ARCHIVES OF OTOLARYNGOLOGY--HEAD & NECK SURGERY 2008; 134:363-9. [PMID: 18427001 PMCID: PMC3342859 DOI: 10.1001/archotol.134.4.363] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
OBJECTIVE To assess tumor markers in advanced laryngeal cancer. DESIGN Marker expression and clinical outcome. PATIENTS Pretreatment tumor biopsy specimens were analyzed from patients enrolled in the Department of Veterans Affairs Laryngeal Cancer Study. MAIN OUTCOME MEASURES Expression of p53 (OMIM TP53) and Bcl-xL (OMIM 600039) in pretreatment biopsy specimens was assessed for correlation with chemotherapy response, laryngeal preservation, and survival. RESULTS Higher rates of larynx preservation were observed in patients whose tumors expressed p53 vs those that did not (80% [36 of 45 patients] vs 59% [24 of 41 patients], P =.03). Higher rates of larynx preservation were also observed in patients whose tumors expressed low levels of Bcl-xL vs high levels of Bcl-xL (90% [18 of 20 patients] vs 60% [30 of 50 patients], P =.02). Patients were categorized into 3 risk groups (low, intermediate, and high) based on their tumor p53 and Bcl-xL expression status. Patients whose tumors had the high-risk biomarker profile (low p53 expression and high Bcl-xL expression) were less likely to preserve their larynx than patients whose tumors had the intermediate-risk biomarker profile (high p53 expression and low or high Bcl-xL expression) or the low-risk biomarker profile (low p53 expression and low Bcl-xL expression). The larynx preservation rates were 100% (10 of 10 patients), 77% (26 of 34 patients), and 54% (7 of 13 patients) for the low-risk, intermediate-risk, and high-risk groups, respectively (P =.04, Fisher exact test). CONCLUSION Tumor expression of p53 and Bcl-xL is a strong predictor of successful larynx preservation in patients treated with induction chemotherapy and followed by radiation therapy in responding tumors.
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Affiliation(s)
- Bhavna Kumar
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI (Ms Kumar, Drs. Prince, Adams, Wolf, Carey, Bradford); Department of Pathology and Department of Periodontics and Oral Medicine, University of Michigan Dental School, Ann Arbor (Drs. Cordell and D’Silva); Department of Community & Preventive Medicine, University of Rochester, Rochester, NY (Dr. Fisher)
| | - Kitrina G. Cordell
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI (Ms Kumar, Drs. Prince, Adams, Wolf, Carey, Bradford); Department of Pathology and Department of Periodontics and Oral Medicine, University of Michigan Dental School, Ann Arbor (Drs. Cordell and D’Silva); Department of Community & Preventive Medicine, University of Rochester, Rochester, NY (Dr. Fisher)
| | - Nisha D’Silva
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI (Ms Kumar, Drs. Prince, Adams, Wolf, Carey, Bradford); Department of Pathology and Department of Periodontics and Oral Medicine, University of Michigan Dental School, Ann Arbor (Drs. Cordell and D’Silva); Department of Community & Preventive Medicine, University of Rochester, Rochester, NY (Dr. Fisher)
| | - Mark E. Prince
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI (Ms Kumar, Drs. Prince, Adams, Wolf, Carey, Bradford); Department of Pathology and Department of Periodontics and Oral Medicine, University of Michigan Dental School, Ann Arbor (Drs. Cordell and D’Silva); Department of Community & Preventive Medicine, University of Rochester, Rochester, NY (Dr. Fisher)
| | - Meredith E. Adams
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI (Ms Kumar, Drs. Prince, Adams, Wolf, Carey, Bradford); Department of Pathology and Department of Periodontics and Oral Medicine, University of Michigan Dental School, Ann Arbor (Drs. Cordell and D’Silva); Department of Community & Preventive Medicine, University of Rochester, Rochester, NY (Dr. Fisher)
| | - Susan G. Fisher
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI (Ms Kumar, Drs. Prince, Adams, Wolf, Carey, Bradford); Department of Pathology and Department of Periodontics and Oral Medicine, University of Michigan Dental School, Ann Arbor (Drs. Cordell and D’Silva); Department of Community & Preventive Medicine, University of Rochester, Rochester, NY (Dr. Fisher)
| | - Gregory T. Wolf
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI (Ms Kumar, Drs. Prince, Adams, Wolf, Carey, Bradford); Department of Pathology and Department of Periodontics and Oral Medicine, University of Michigan Dental School, Ann Arbor (Drs. Cordell and D’Silva); Department of Community & Preventive Medicine, University of Rochester, Rochester, NY (Dr. Fisher)
| | - Thomas E. Carey
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI (Ms Kumar, Drs. Prince, Adams, Wolf, Carey, Bradford); Department of Pathology and Department of Periodontics and Oral Medicine, University of Michigan Dental School, Ann Arbor (Drs. Cordell and D’Silva); Department of Community & Preventive Medicine, University of Rochester, Rochester, NY (Dr. Fisher)
| | - Carol R. Bradford
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI (Ms Kumar, Drs. Prince, Adams, Wolf, Carey, Bradford); Department of Pathology and Department of Periodontics and Oral Medicine, University of Michigan Dental School, Ann Arbor (Drs. Cordell and D’Silva); Department of Community & Preventive Medicine, University of Rochester, Rochester, NY (Dr. Fisher)
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Westra WH, Taube JM, Poeta ML, Begum S, Sidransky D, Koch WM. Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck. Clin Cancer Res 2008; 14:366-9. [PMID: 18223210 DOI: 10.1158/1078-0432.ccr-07-1402] [Citation(s) in RCA: 175] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Squamous cell carcinomas of the head and neck (HNSCC) often harbor p53 mutations, but p53 protein degradation by the viral oncoprotein E6 may supercede p53 mutations in human papillomavirus 16 (HPV16)-positive tumors. The prevalence of p53 mutations in HPV-positive HNSCCs is indeed lower, but in some tumors these alterations coexist. The purpose of this study was to discern whether HNSCCs differ in the type of p53 mutations as a function of HPV16 status. EXPERIMENTAL DESIGN The study was nested within a prospective multicenter study (ECOGE 4393/RTOG R9614) of patients with HNSCC treated surgically with curative intent. Tumors from one study center were used to construct a tissue microarray. The tumors were well characterized with respect to p53 mutational status. The tissue microarray was evaluated by HPV16 in situ hybridization. HPV16 analysis was also done on a select group of tonsillar carcinomas known to harbor disruptive p53 mutations defined as stop mutations or nonconservative mutations within the DNA binding domain. RESULTS HPV16 was detected in 12 of 89 (13%) HNSCCs. By tumor site, HPV16 was detected in 12 of 21 (57%) tumors from the palatine/lingual tonsils, but in none of 68 tumors from nontonsillar sites (P < 0.00001). Both HPV16-positive and HPV16-negative HNSCCs harbored p53 mutations (25% versus 52%), but disruptive mutations were only encountered in HPV16-negative carcinomas. Of seven tonsillar carcinomas with disruptive p53 mutations, none were HPV16 positive, in contrast to HPV16-positive tonsillar carcinomas without disruptive p53 mutations (0% versus 57%; P = 0.008). CONCLUSIONS Although HPV16 and mutated p53 may coexist in a subset of HNSCCs, HPV16 and disruptive p53 mutations seem to be nonoverlapping events. A less calamitous genetic profile, including the absence of disruptive p53 mutations, may underlie the emerging clinical profile of HPV16-positive HNSCC such as improved patient outcome.
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Affiliation(s)
- William H Westra
- Department of Pathology and Otolaryngology, Head and Neck Surgery (Division of Head and Neck Cancer Research), The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
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Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, Ridge JA, Goodwin J, Kenady D, Saunders J, Westra W, Sidransky D, Koch WM. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med 2007; 357:2552-61. [PMID: 18094376 PMCID: PMC2263014 DOI: 10.1056/nejmoa073770] [Citation(s) in RCA: 573] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND The abrogation of function of the tumor-suppressor protein p53 as a result of mutation of its gene, TP53, is one of the most common genetic alterations in cancer cells. We evaluated TP53 mutations and survival in patients with squamous-cell carcinoma of the head and neck. METHODS A total of 560 patients with squamous-cell carcinoma of the head and neck who were treated surgically with curative intent were enrolled in our prospective multicenter, 7-year study. TP53 mutations were analyzed in DNA from the tumor specimens with the use of the Affymetrix p53 chip and the Surveyor DNA endonuclease and denaturing high-performance liquid chromatography. Mutations were classified into two groups, disruptive and nondisruptive, according to the degree of disturbance of protein structure predicted from the crystal structure of the p53-DNA complexes. TP53 mutational status was compared with clinical outcome. RESULTS TP53 mutations were found in tumors from 224 of 420 patients (53.3%). As compared with wild-type TP53, the presence of any TP53 mutation was associated with decreased overall survival (hazard ratio for death, 1.4; 95% confidence interval [CI], 1.1 to 1.8; P=0.009), with an even stronger association with disruptive mutations (hazard ratio, 1.7; 95% CI, 1.3 to 2.4; P<0.001) and no significant association with nondisruptive mutations (hazard ratio, 1.2; 95% CI, 0.9 to 1.7; P=0.16). In multivariate analyses a disruptive TP53 alteration, as compared with the absence of a TP53 mutation, had an independent, significant association with decreased survival (hazard ratio, 1.7; 95% CI, 1.2 to 2.4; P=0.003). CONCLUSIONS Disruptive TP53 mutations in tumor DNA are associated with reduced survival after surgical treatment of squamous-cell carcinoma of the head and neck.
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Strano S, Dell'Orso S, Mongiovi AM, Monti O, Lapi E, Di Agostino S, Fontemaggi G, Blandino G. Mutant p53 proteins: between loss and gain of function. Head Neck 2007; 29:488-96. [PMID: 17123310 DOI: 10.1002/hed.20531] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Cancer might result from both the aberrant activation of genes, whose physiological tuning is essential for the life of a normal cell, and the inactivation of tumor suppressor genes, whose main job is to preserve the integrity of cell genome. Among the latter, p53 is considered a key tumor suppressor gene that is inactivated mainly by missense mutations in half of human cancers. It is becoming increasingly clear that the resulting mutant p53 proteins gain oncogenic properties favoring the insurgence, the maintenance, and the spreading of malignant tumors. In this review, we mainly discuss the molecular mechanisms underlying gain of function of human tumor-derived p53 mutants, their impact on the chemoresistance and the prognosis of human tumors, with a special focus on head and neck cancers, and the perspectives of treating tumors through the manipulation of mutant p53 proteins.
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Affiliation(s)
- Sabrina Strano
- Department of Experimental Oncology, Regina Elena Cancer Institute, 00158 Rome, Italy
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50
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McCaul JA, Gordon KE, Minty F, Fleming J, Parkinson EK. Telomere dysfunction is related to the intrinsic radio-resistance of human oral cancer cells. Oral Oncol 2007; 44:261-9. [PMID: 17475542 DOI: 10.1016/j.oraloncology.2007.02.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2006] [Revised: 02/23/2007] [Accepted: 02/23/2007] [Indexed: 12/27/2022]
Abstract
Evidence from telomerase-deficient mice strongly suggests that dysfunctional short telomeres affect cellular radio-sensitivity but this idea has yet to be extensively tested in relevant human cancer types such as oral squamous cell carcinomas (OSCCs), which are frequently treated by radiotherapy. The OSCC line BICR7 has low levels of telomerase activity, short telomeres and high levels of telomere dysfunction (judged by a high level of anaphase bridges); whereas the BICR6 line has high levels of telomerase and is more radio-resistant. Ectopic expression of the human TElomerase Reverse Transcriptase (hTERT) reduced telomere dysfunction and increased radio-resistance in BICR7 cells, but not BICR6. Furthermore, the radio-resistance of GM847 cells, which use telomerase-independent mechanisms of telomere maintenance, and of telomerase-negative normal human fibroblasts with long telomeres are similarly unaffected by ectopic expression of telomerase. We tested whether telomere function, as measured by the Anaphase Bridge Index (ABI), was found to be a useful predictor of radio-resistance in a panel of OSCC lines. Using inverse regression analysis, we found a strong inverse relationship between the ABI and radio-resistance (P<0.001), as measured by the Surviving Fraction at 4Gy (SF4). These results suggest that telomerase inhibitors could sensitise a subset of oral SCCs with short telomeres to radiotherapy and for the first time demonstrate that the tumour ABI may assist the selection of cancers that would be suitable for such sensitisation therapy.
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Affiliation(s)
- James A McCaul
- Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Rd., Bearsden, Glasgow G61 1BD, UK
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