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Islam SS, Karakas B, Aboussekhra A, Noman ASM. KEAP1/NRF2 Mutations in Stem Cells Define an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure. Cancers (Basel) 2023; 15:5006. [PMID: 37894373 PMCID: PMC10605399 DOI: 10.3390/cancers15205006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/05/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
Mutations in Keap1/Nrf2 in head and neck cancer result in abnormal cell growth. Progenitor cells, bulk tumor cells, and head and neck cancer stem cells (HN-CSCs) may all harbor these mutations. Nevertheless, whether Keap1/Nrf2 mutations in HN-CSCs have an impact on clinical outcomes is unknown. Cancerous HN-CSCs and benign stem cells were obtained from freshly resected head and neck cancer patients (n = 50) via flow cytometry cell sorting and tested for Keap1/Nrf2 mutations. The existence of Keap1/Nrf2 mutations in HN-CSCs, as well as their correlations with tumor mutations, pathologic tumor stage, tumor histologic grades, lung metastasis, treatment outcomes, and the patient's age and conditions, are assessed at the last follow-up visit. Thirteen tumors were found to have Keap1/Nrf2 mutations in their HN-CSCs. More than half of the lung metastases and disease progression occurred in HN-CSCs with mutations. Patients whose tumors carried Keap1/Nrf2 mutations in their HN-CSCs had significantly shorter progression-free survival, overall survival, and time of treatment failure than their non-HN-CSC counterparts. These associations were partly driven by HN-CSCs, in which Keap1/Nrf2 mutations were overrepresented in fast progressors and associated with an increased risk of disease progression. Our findings suggest that molecular genotyping of HN-CSCs may facilitate personalized treatment strategies and assist in identifying patients who are likely to benefit from chemotherapy.
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Affiliation(s)
- Syed S. Islam
- Department Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
- Faculty of Medicine, Al-Faisal University, Riyadh 11533, Saudi Arabia
| | - Bedri Karakas
- 3 B & B Bio, 4 Professional Drive, Gaithersburg, MD 20879, USA;
| | - Abdelilah Aboussekhra
- Department Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Abu Shadat M. Noman
- Department Biochemistry and Molecular Biology, The University of Chittagong, Chittagong 4331, Bangladesh
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Lai TY, Ko YC, Chen YL, Lin SF. The Way to Malignant Transformation: Can Epigenetic Alterations Be Used to Diagnose Early-Stage Head and Neck Cancer? Biomedicines 2023; 11:1717. [PMID: 37371812 PMCID: PMC10296077 DOI: 10.3390/biomedicines11061717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/05/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Identifying and treating tumors early is the key to secondary prevention in cancer control. At present, prevention of oral cancer is still challenging because the molecular drivers responsible for malignant transformation of the 11 clinically defined oral potentially malignant disorders are still unknown. In this review, we focused on studies that elucidate the epigenetic alterations demarcating malignant and nonmalignant epigenomes and prioritized findings from clinical samples. Head and neck included, the genomes of many cancer types are largely hypomethylated and accompanied by focal hypermethylation on certain specific regions. We revisited prior studies that demonstrated that sufficient uptake of folate, the primary dietary methyl donor, is associated with oral cancer reduction. As epigenetically driven phenotypic plasticity, a newly recognized hallmark of cancer, has been linked to tumor initiation, cell fate determination, and drug resistance, we discussed prior findings that might be associated with this hallmark, including gene clusters (11q13.3, 19q13.43, 20q11.2, 22q11-13) with great potential for oral cancer biomarkers, and successful examples in screening early-stage nasopharyngeal carcinoma. Although one-size-fits-all approaches have been shown to be ineffective in most cancer therapies, the rapid development of epigenome sequencing methods raises the possibility that this nonmutagenic approach may be an exception. Only time will tell.
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Affiliation(s)
- Ting-Yu Lai
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan;
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
| | - Ying-Chieh Ko
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
| | - Yu-Lian Chen
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
| | - Su-Fang Lin
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan; (Y.-C.K.); (Y.-L.C.)
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Wahbi W, Korelin K, Sieviläinen M, Karihtala P, Wilkman T, Tarkkanen J, Salo T, Al-Samadi A. Evaluation of in vitro and in vivo personalized cancer treatment assays for oral squamous cell carcinoma. Transl Oncol 2023; 33:101677. [PMID: 37099957 PMCID: PMC10182324 DOI: 10.1016/j.tranon.2023.101677] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/28/2023] [Accepted: 04/14/2023] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is a common cancer with a high heterogeneity and few approved treatments. OSCC is one of the least explored areas for precision oncology. In this study, we aimed to test the reliability of our three established rapid cancer systemic treatment-testing assays: human tumour-derived matrix (Myogel)-coated well-plates, zebrafish xenografts, and 3D microfluidic chips. METHODS Chemo-, radio- and targeted-therapy testing in Myogel-coated wells and zebrafish xenografts was conducted nine times using five samples; two primary and three metastatic lymph node samples from three OSCC patients. Peripheral blood mononuclear cells (PBMNCs) were isolated from the patients' blood. The response of the tumour cells to radio-, chemo-, and targeted therapy was tested using Myogel-coated wells and zebrafish larvae xenografts. The tumour cells' response to immunotherapy was tested using 3D microfluidic chips. The cells' sensitivity to the treatments was compared with the patients' clinical response. Primary and metastatic lymph node tissue-derived DNA samples from two patients underwent whole exome sequencing to compare the mutational profiles of the samples. RESULTS Test results were in line with patients' responses in 7/9 (77%) zebrafish xenograft assays and 5/9 (55%) Myogel-coated wells assays. Immunotherapy testing was done using one metastatic patient sample which matched the patients' response. Differences in responses to treatments between primary and metastatic samples of the same patient were detected in 50% of the zebrafish larvae assays. CONCLUSIONS Our results show the potential of using personalized cancer treatment testing assays - specifically zebrafish xenografts that revealed promising results - in OSCC patient samples.
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Affiliation(s)
- Wafa Wahbi
- Department of Oral and Maxillofacial Diseases, Clinicum, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki 1, C223b, Haartmaninkatu 8, P.O. Box 63, Helsinki 00014, Finland; Translational Immunology Research Program (TRIMM), Faculty of Medicine, University of Helsinki, Biomedicum Helsinki 1, Haartmaninkatu 8, P.O. Box 63, Helsinki 00014, Finland
| | - Katja Korelin
- Department of Oral and Maxillofacial Diseases, Clinicum, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki 1, C223b, Haartmaninkatu 8, P.O. Box 63, Helsinki 00014, Finland; Translational Immunology Research Program (TRIMM), Faculty of Medicine, University of Helsinki, Biomedicum Helsinki 1, Haartmaninkatu 8, P.O. Box 63, Helsinki 00014, Finland
| | - Meri Sieviläinen
- Department of Oral and Maxillofacial Diseases, Clinicum, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki 1, C223b, Haartmaninkatu 8, P.O. Box 63, Helsinki 00014, Finland; Translational Immunology Research Program (TRIMM), Faculty of Medicine, University of Helsinki, Biomedicum Helsinki 1, Haartmaninkatu 8, P.O. Box 63, Helsinki 00014, Finland
| | - Peeter Karihtala
- Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center and University of Helsinki, P.O. Box 180, Helsinki 00029, Finland
| | - Tommy Wilkman
- Department of Oral and Maxillofacial Surgery, HUS Helsinki University Hospital, P.O. Box 281, Helsinki 00029, Finland
| | - Jussi Tarkkanen
- Department of Pathology, HUSLAB, University of Helsinki and Helsinki University Hospital, P.O. Box 21, Helsinki, 00014, Finland
| | - Tuula Salo
- Department of Oral and Maxillofacial Diseases, Clinicum, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki 1, C223b, Haartmaninkatu 8, P.O. Box 63, Helsinki 00014, Finland; Translational Immunology Research Program (TRIMM), Faculty of Medicine, University of Helsinki, Biomedicum Helsinki 1, Haartmaninkatu 8, P.O. Box 63, Helsinki 00014, Finland; Department of Pathology, HUSLAB, University of Helsinki and Helsinki University Hospital, P.O. Box 21, Helsinki, 00014, Finland; Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, P.O. Box 5281, Oulu 90014, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 5281, Oulu 90014, Finland
| | - Ahmed Al-Samadi
- Department of Oral and Maxillofacial Diseases, Clinicum, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki 1, C223b, Haartmaninkatu 8, P.O. Box 63, Helsinki 00014, Finland; Translational Immunology Research Program (TRIMM), Faculty of Medicine, University of Helsinki, Biomedicum Helsinki 1, Haartmaninkatu 8, P.O. Box 63, Helsinki 00014, Finland.
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Daneste H, Sadeghzadeh A, Mokhtari M, Mohammadkhani H, Lavaee F, Moayedi J. Immunoexpression of p53 mutant-type in Iranian patients with primary and recurrence oral squamous cell carcinoma. Eur J Transl Myol 2022; 33:10847. [PMID: 36413207 PMCID: PMC10141754 DOI: 10.4081/ejtm.2022.10847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/10/2022] [Indexed: 11/23/2022] Open
Abstract
Mutations in tumor suppressor p53 protein can occur at different phases of malignant transformation and affect the patient's prognosis. This study aimed to evaluate the expression of mutant p53 protein in Iranian patients with the primary and recurrence oral squamous cell carcinoma (OSCC). This retrospective cross-sectional study conducted on a group of patients with the primary OSCC (n=122) and the control subjects with oral noncancerous reactive lesions (n=80). Immunohistochemistry was performed with the DO-7 monoclonal antibody against p53 protein, and samples with ≥10% immunostaining were considered positive. Statistical analyses were carried out using SPSS. Positive staining for p53 was observed in none of the control subjects and 57.4% (70 of 122) of the primary OSCC patients (p<0.0001, OR=107.69, 95%CI=6.49-179.0). The p53 immunopositivity had no significant differences between males and females (54.2% vs. 62%, p=0.390), but significantly different between those aged below and over 50 years (p<0.0001, OR=4.52, 95%CI=1.07-12.05). During follow-up, OSCC recurrence occurred in 104 patients, but the phenotype of the mutant p53 protein in patients who relapsed was the same as in matched primary tumors (p=0.763). Risk of recurrence had no significant differences between p53-positive and p53-negative cases (p=0.953), males and females (p=0.263), and age below and over 50 years (p=0.223). Despite its confirmed diagnostic value, the immunoexpression of the p53 mutant protein in OSCC in cancer recurrence was the same as in the primary tumor. However, further studies with a larger sample size and longer follow-up are needed to confirm or change our conclusions.
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Affiliation(s)
- Hossein Daneste
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Shiraz University of Medical Sciences, Shiraz.
| | - Azita Sadeghzadeh
- Oral and Dental Disease Research Center, Department of Oral and Maxillofacial Medicine, School of Dentistry, Shiraz University of Medical Sciences, Shiraz.
| | - Maral Mokhtari
- Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz.
| | - Hossein Mohammadkhani
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Shiraz University of Medical Sciences, Shiraz.
| | - Fatemeh Lavaee
- Oral and Dental Disease Research Center, Department of Oral and Maxillofacial Medicine, School of Dentistry, Shiraz University of Medical Sciences, Shiraz.
| | - Javad Moayedi
- Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz.
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Paracchini L, Beltrame L, Grassi T, Inglesi A, Fruscio R, Landoni F, Ippolito D, Delle Marchette M, Paderno M, Adorni M, Jaconi M, Romualdi C, D'Incalci M, Siravegna G, Marchini S. Genome-wide Copy-number Alterations in Circulating Tumor DNA as a Novel Biomarker for Patients with High-grade Serous Ovarian Cancer. Clin Cancer Res 2021; 27:2549-2559. [PMID: 33323403 DOI: 10.1158/1078-0432.ccr-20-3345] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/27/2020] [Accepted: 12/11/2020] [Indexed: 02/05/2023]
Abstract
PURPOSE High-grade serous epithelial ovarian cancer (HGS-EOC) is defined by high levels of somatic copy-number alterations (SCNA) with marked spatial and temporal tumor heterogeneity. Biomarkers serving to monitor drug response and detect disease recurrence are lacking, a fact which reflects an unmet clinical need. EXPERIMENTAL DESIGN A total of 185 plasma samples and 109 matched tumor biopsies were collected from 46 patients with HGS-EOC, and analyzed by shallow whole-genome sequencing (sWGS). The percentage of tumor fraction (TF) in the plasma was used to study the biological features of the disease at the time of diagnosis (T0) and correlated with patients' survival. Longitudinal analysis of TF was correlated with CA-125 levels and radiological images to monitor disease recurrence. RESULTS Gain in the clonal regions, 3q26.2 and 8q24.3, was observed in the 87.8% and 78.05% of plasma samples, suggesting that plasma sWGS mirrors solid biopsies. At T0, multivariate analysis revealed that plasma TF levels were an independent prognostic marker of relapse (P < 0.022). After platinum (Pt)-based treatment, circulating tumor DNA (ctDNA) analysis showed a change in the heterogeneous pattern of genomic amplification, including an increased frequency of amplification, compared with before Pt-based treatment in the 19p31.11 and 19q13.42 regions. TF in serially collected ctDNA samples outperformed CA-125 in anticipating clinical and radiological progression by 240 days (range, 37-491). CONCLUSIONS Our results support the notion that sWGS is an inexpensive and useful tool for the genomic analysis of ctDNA in patients with HGS-EOC to monitor disease evolution and to anticipate relapse better than serum CA-125, the routinely used clinical biomarker.See related commentary by Dhani, p. 2372.
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Affiliation(s)
- Lara Paracchini
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Luca Beltrame
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Tommaso Grassi
- Department of Obstetrics and Gynaecology, Università degli Studi Milano-Bicocca, San Gerardo Hospital, Monza, Italy
| | - Alessia Inglesi
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Robert Fruscio
- Department of Obstetrics and Gynaecology, Università degli Studi Milano-Bicocca, San Gerardo Hospital, Monza, Italy
| | - Fabio Landoni
- Department of Obstetrics and Gynaecology, Università degli Studi Milano-Bicocca, San Gerardo Hospital, Monza, Italy
| | - Davide Ippolito
- Department of Obstetrics and Gynaecology, Università degli Studi Milano-Bicocca, San Gerardo Hospital, Monza, Italy
| | - Martina Delle Marchette
- Department of Obstetrics and Gynaecology, Università degli Studi Milano-Bicocca, San Gerardo Hospital, Monza, Italy
| | - Mariachiara Paderno
- Department of Obstetrics and Gynaecology, Università degli Studi Milano-Bicocca, San Gerardo Hospital, Monza, Italy
| | - Marco Adorni
- Department of Obstetrics and Gynaecology, Università degli Studi Milano-Bicocca, San Gerardo Hospital, Monza, Italy
| | - Marta Jaconi
- Department of Pathology, Università degli Studi Milano-Bicocca, San Gerardo Hospital, Monza, Italy
| | | | - Maurizio D'Incalci
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
| | - Giulia Siravegna
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Sergio Marchini
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
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Moura ACD, Assad DX, Amorim Dos Santos J, Porto de Toledo I, Barra GB, Castilho RM, Squarize CH, Guerra ENS. Worldwide prevalence of PI3K-AKT-mTOR pathway mutations in head and neck cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2021; 160:103284. [PMID: 33675910 DOI: 10.1016/j.critrevonc.2021.103284] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 02/03/2021] [Accepted: 02/27/2021] [Indexed: 02/07/2023] Open
Abstract
A systematic review (SR) and meta-analysis were conducted to determine the prevalence of PI3K-AKT-mTOR signaling pathway mutations in patients with head and neck cancer (HNC). Overall, 105 studies comprising 8630 patients and 1306 mutations were selected. The estimated mutations prevalence was 13 % for PIK3CA (95 % confidence interval [CI] = 11-14; I2 = 82 %; p < 0.0001), 4% for PTEN (95 % CI = 3-5; I2 = 55 %; p < 0.0001), 3% for MTOR (95 % CI = 2-4; I2 = 5%; p = 0.40), and 2% for AKT (95 % CI = 1-2; I2 = 50 %; p = 0.0001). We further stratified the available data of the participants according to risk factors and tumor characteristics, including HPV infection, tobacco use, alcohol exposure, TNM stage, and histological tumor differentiation, and performed subgroup analysis. We identified significant associations between PI3K-AKT-mTOR pathway-associated mutations and advanced TNM stage (odds ratio [OR] = 0.20; 95 % CI = 0.09-0.44; I² = 71 %; p = 0.0001) and oropharyngeal HPV-positive tumors and PIK3CA mutations (OR = 17.48; 95 % CI = 4.20-72.76; I² = 69 %; p < 0.0002). No associations were found between alcohol and tobacco exposure, and tumor differentiation grade. This SR demonstrated that the PI3K-AKT-mTOR pathway emerges as a potential prognostic factor and could offer a molecular basis for future studies on therapeutic targeting in HNC patients.
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Affiliation(s)
- Adriana Castelo de Moura
- Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília, Brasília, Brazil; Hospital Universitário de Brasília (HUB-UnB/Ebserh), Brasília, DF, Brazil; Hospital Santa Lúcia, Brasília, DF, Brazil
| | - Daniele Xavier Assad
- Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília, Brasília, Brazil; Medical Oncology Department, Hospital Sírio-Libanês, Brasília, DF, Brazil
| | - Juliana Amorim Dos Santos
- Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília, Brasília, Brazil
| | - Isabela Porto de Toledo
- Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília, Brasília, Brazil
| | - Gustavo Barcelos Barra
- Sabin Medicina Diagnóstica, SAAN Quadra 03 Lotes 145/185, Brasília, 70632-340, DF, Brazil
| | - Rogerio Moraes Castilho
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, Division of Oral Pathology, Radiology and Medicine, University of Michigan School of Dentistry. Ann Arbor, 48109-1078, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Cristiane Helena Squarize
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, Division of Oral Pathology, Radiology and Medicine, University of Michigan School of Dentistry. Ann Arbor, 48109-1078, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Eliete Neves Silva Guerra
- Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília, Brasília, Brazil; Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, Division of Oral Pathology, Radiology and Medicine, University of Michigan School of Dentistry. Ann Arbor, 48109-1078, MI, USA.
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Alvarado-Muñoz JF, Falco A, Morales AR, Sánchez NC, Reynoso G, Barillas A, Moreno J, López K, Prestol R, Cabreja A, Nuñez C. Platinum ineligibility in squamous cell carcinoma of the head and neck: consensus from Central America and the Caribbean. Future Oncol 2021; 17:1963-1971. [PMID: 33559505 DOI: 10.2217/fon-2020-0931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The high incidence of head and neck cancer in Central America and the Caribbean, together with limitations in the healthcare system for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) in this region necessitate a consensus of opinion based on a review of the literature on therapy with cisplatin plus radiation. Such an approach will ensure appropriate selection of patients who can benefit from therapy and reduce the incidence of related adverse events. Therefore, we recorded the opinion of experts in the region in order to identify needs and challenges in the treatment of LA SCCHN.
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Affiliation(s)
| | - Agustín Falco
- Alexander Fleming Institute of Oncology, Buenos Aires, Argentina
| | | | - Noé C Sánchez
- Guatemalan Social Security Institute, Guatemala City, Guatemala
| | | | - Allan Barillas
- Guatemalan Social Security Institute, Guatemala City, Guatemala
| | | | - Kreilin López
- Heriberto Pieter Cancer Institute, Santo Domingo, Dominican Republic
| | - Rogelio Prestol
- Heriberto Pieter Cancer Institute, Santo Domingo, Dominican Republic
| | - Angela Cabreja
- Regional Oncological Institute Cibao, Santiago de los Caballeros, Dominican Republic
| | - César Nuñez
- Regional Oncological Institute Cibao, Santiago de los Caballeros, Dominican Republic
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de Lima NRB, de Souza Junior FG, Roullin VG, Pal K, da Silva ND. Head and Neck Cancer Treatments from Chemotherapy to Magnetic Systems: Perspectives and Challenges. Curr Radiopharm 2021; 15:2-20. [PMID: 33511961 DOI: 10.2174/1874471014999210128183231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/13/2020] [Accepted: 11/18/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cancer is one of the diseases causing society's fears as a stigma of death and pain. Head and Neck Squamous Cell Carcinoma (HNSCC) is a group of malignant neoplasms of different locations in this region of the human body. It is one of the leading causes of morbidity and mortality in Brazil, because these malignant neoplasias, in most cases, are diagnosed in late phases. Surgical excision, chemotherapy and radiotherapy encompass the forefront of antineoplastic therapy; however, the numerous side effects associated with these therapeutic modalities are well known. Some treatments present enough potential to help or replace conventional treatments, such as Magnetic Hyperthermia and Photodynamic Therapy. Such approaches require the development of new materials at the nanoscale, able to carry out the loading of their active components while presenting characteristics of biocompatibility mandatory for biomedical applications. OBJECTIVE This work aims to make a bibliographical review of HNSCC treatments. Recent techniques proven effective in other types of cancer were highlighted and raised discussion and reflections on current methods and possibilities of enhancing the treatment of HNSCC. METHOD The study was based on a bibliometric research between the years 2008 and 2019 using the following keywords: Cancer, Head and Neck Cancer, Chemotherapy, Radiotherapy, Photodynamic Therapy, and Hyperthermia. RESULTS A total of 5.151.725 articles were found, 3.712.670 about cancer, 175.470 on Head and Neck Cancer, 398.736 on Radiotherapy, 760.497 on Chemotherapy, 53.830 on Hyperthermia, and 50.522 on Photodynamic Therapy. CONCLUSION The analysis shows that there is still much room for expanding research, especially for alternative therapies since most of the studies still focus on conventional treatments and on the quest to overcome their side effects. The scientific community needs to keep looking for more effective therapies generating fewer side effects for the patient. Currently, the so-called alternative therapies are being used in combination with the conventional ones, but the association of these new therapies shows great potential, in other types of cancer, to improve the treatment efficacy.
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Affiliation(s)
- Nathali R B de Lima
- Biopolymer & Sensors Lab. - Instituto de Macromoléculas Professora Eloisa Mano, Centro de Tecnologia-Cidade Universitária, Av. Horacio Macedo, 2030, bloco J. Universidade Federal de Rio de Janeiro, Zip code 21941-909,. Brazil
| | - Fernando G de Souza Junior
- Biopolymer & Sensors Lab. - Instituto de Macromoléculas Professora Eloisa Mano, Centro de Tecnologia-Cidade Universitária, Av. Horacio Macedo, 2030, bloco J. Universidade Federal de Rio de Janeiro, Zip code 21941-909,. Brazil
| | - Valérie G Roullin
- Faculté de Pharmacie Université de Montréal, Pavillon Jean-Coutu, 2940 chemin de la polytechnique Montreal QC, H3T 1J4,. Canada
| | - Kaushik Pal
- Wuhan University, Hubei Province, 8 East Lake South Road. Wuchang 430072,. China
| | - Nathalia D da Silva
- Programa de Engenharia da Nanotecnologia, COPPE, Centro de Tecnologia-Cidade Universitária, Av. Horacio Macedo, 2030, bloco I. Universidade Federal de Rio de Janeiro,. Brazil
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9
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Shah PA, Huang C, Li Q, Kazi SA, Byers LA, Wang J, Johnson FM, Frederick MJ. NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma. Cells 2020; 9:cells9122677. [PMID: 33322834 PMCID: PMC7764697 DOI: 10.3390/cells9122677] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022] Open
Abstract
Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1's role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer's genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.
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Affiliation(s)
- Pooja A. Shah
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.A.S.); (L.A.B.)
| | - Chenfei Huang
- Bobby R. Alford Department of Otolaryngology, Baylor College of Medicine, Houston, TX 77030, USA; (C.H.); (M.J.F.)
| | - Qiuli Li
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
| | - Sawad A. Kazi
- School of Natural Sciences, University of Texas, Austin, TX 78712, USA;
| | - Lauren A. Byers
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.A.S.); (L.A.B.)
- The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA;
| | - Jing Wang
- The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA;
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Faye M. Johnson
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.A.S.); (L.A.B.)
- The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA;
- Correspondence: ; Tel.: +1-713–792-6363; Fax: +1-713-792-1220
| | - Mitchell J. Frederick
- Bobby R. Alford Department of Otolaryngology, Baylor College of Medicine, Houston, TX 77030, USA; (C.H.); (M.J.F.)
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10
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Facompre ND, Rajagopalan P, Sahu V, Pearson AT, Montone KT, James CD, Gleber-Netto FO, Weinstein GS, Jalaly J, Lin A, Rustgi AK, Nakagawa H, Califano JA, Pickering CR, White EA, Windle BE, Morgan IM, Cohen RB, Gimotty PA, Basu D. Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models. Int J Cancer 2020; 147:3236-3249. [PMID: 32478869 DOI: 10.1002/ijc.33125] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 04/25/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023]
Abstract
Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. Our study establishes the first well-characterized panel of patient-derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotype-phenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster-growing models facilitated identification of a novel association between TMB and local progression in both HPV+ and HPV- patients that was prognostic in HPV- cases. In addition, reduced E7 and p16INK4A levels found in a PDX from an outlier case with lethal outcome led to detection of similar profiles among recurrent HPV+ HNSCCs. Transcriptional data from the Cancer Genome Atlas was used to demonstrate that the lower E2F target gene expression predicted by reduced E7 levels has potential as a biomarker of disease recurrence risk. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel potential applications of quantifying mutational burden and viral oncogene functions for biomarker development.
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Affiliation(s)
- Nicole D Facompre
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Pavithra Rajagopalan
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Varun Sahu
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Kathleen T Montone
- Department of Pathology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Claire D James
- School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | | | - Gregory S Weinstein
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jalal Jalaly
- Department of Pathology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alexander Lin
- Department of Radiation Oncology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Anil K Rustgi
- Department of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hiroshi Nakagawa
- Department of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joseph A Califano
- Department of Surgery, University of California San Diego, San Diego, California, USA
| | - Curtis R Pickering
- Department of Head and Neck Surgery, The MD Anderson Cancer Center, Houston, Texas, USA
| | - Elizabeth A White
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Bradford E Windle
- School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Iain M Morgan
- School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Roger B Cohen
- Department of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Phyllis A Gimotty
- Department of Biostatistics, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Devraj Basu
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.,The Wistar Institute, Philadelphia, Pennsylvania, USA
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11
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Chintala S, Levan J, Robinson K, Quist K, Katzenellenbogen RA. Genes Regulated by HPV 16 E6 and High Expression of NFX1-123 in Cervical Cancers. Onco Targets Ther 2020; 13:6143-6156. [PMID: 32617009 PMCID: PMC7326398 DOI: 10.2147/ott.s251926] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 05/18/2020] [Indexed: 11/23/2022] Open
Abstract
Purpose High-risk human papillomaviruses (HR HPV) cause cervical cancer, and in these cancers, HPV type 16 is the most common HR type. The HR viral oncogenes E6 and E7 partner with cellular proteins to drive cancer and modulate immune pathways; previously, we demonstrated in keratinocytes that HPV 16 E6 and high expression of the endogenous host protein partner NFX1-123 led to the increased expression of multiple genes, including Notch1, secretory leukocyte peptidase inhibitor (SLPI), and retinoic acid early transcript 1G (RAET1G). The present study was conducted to determine if NFX1-123 was highly expressed in cervical cancer and if genes increased by NFX1-123 and 16E6 in keratinocytes were also increased in cervical cancers. Materials and Methods The Cancer Genome Atlas (TCGA) database and The Human Protein Atlas database were used to compare relative mRNA and protein gene expression, respectively, in the normal cervix and cervical cancers. Formalin-fixed paraffin-embedded (FFPE) normal cervix and HPV 16 positive cervical cancer samples were analyzed for relative protein expression by immunohistochemical staining. Protein expression of a subset of regulated genes was quantified by Western blot of HPV positive and negative cell lines. Results Immunohistochemical staining of HPV 16 positive cervical dysplasias and cancers revealed high NFX1-123, Ki67, and Notch1 expression. NFX1 and NFX1L1 mRNA levels were increased in cervical cancers compared to normal cervix in the TCGA database. Fourteen genes previously identified as upregulated in keratinocytes with 16E6 and overexpressed NFX1-123 also had high mRNA expression and selected genes had high protein expression in cervical cancers and cell lines. Conclusion In cervical cancer, NFX1-123 is highly expressed, and 16E6 and NFX1-123 together alter the expression of a wide set of genes. The involvement of these genes in cell proliferation, differentiation, invasion, and metastasis provides further insight into potential ways that HR HPVs promote cancer initiation and maintenance.
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Affiliation(s)
- Sreenivasulu Chintala
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Justine Levan
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kristin Robinson
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kevin Quist
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
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12
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de Carvalho AC, Perdomo S, Dos Santos W, Fernandes GC, de Jesus LM, Carvalho RS, Scapulatempo-Neto C, de Almeida GC, Sorroche BP, Arantes LMRB, Melendez ME, De Marchi P, Hayes N, Reis RM, Carvalho AL. Impact of genetic variants in clinical outcome of a cohort of patients with oropharyngeal squamous cell carcinoma. Sci Rep 2020; 10:9970. [PMID: 32561788 PMCID: PMC7305218 DOI: 10.1038/s41598-020-66741-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023] Open
Abstract
Tobacco- or human papillomavirus- driven oropharyngeal squamous cell carcinomas (OpSCC) represent distinct clinical, biological and epidemiological entities. The aim of this study was to identify genetic variants based on somatic alterations in OpSCC samples from an admixed population, and to test for association with clinical features. The entire coding region of 15 OpSCC driver genes was sequenced by next-generation sequencing in 51 OpSCC FFPE samples. Thirty-five percent of the patients (18/51) were HPV-positive and current or past tobacco consumption was reported in 86.3% (44/51). The mutation profile identified an average of 2.67 variants per sample. Sixty-three percent of patients (32/51; 62.7%) were mutated for at least one of the genes tested and TP53 was the most frequently mutated gene. The presence of mutation in NOTCH1 and PTEN, significantly decreased patient's recurrence-free survival, but only NOTCH1 mutation remained significant after stepwise selection, with a risk of recurrence of 4.5 (HR 95% CI = 1.11-14.57; Cox Regression p = 0.034). These results show that Brazilian OpSCC patients exhibit a similar clinical and genetic profile in comparison to other populations. Molecular characterization is a promising tool for the definition of clinical subgroups, aiding in a more precise tailoring of treatment and prognostication.
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Affiliation(s)
| | - Sandra Perdomo
- Institute of Nutrition, Genetics and Metabolism Research, Faculty of Medicine, Universidad El Bosque, Bogotá, Colombia
- International Agency of Research on Cancer, Lyon, France
| | | | | | | | | | - Cristovam Scapulatempo-Neto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Pathology and Molecular Diagnostics Service, Diagnósticos da América-DASA, São Paulo, SP, Brazil
| | | | | | | | - Matias Eliseo Melendez
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Pelé Little Prince Research Institute, Curitiba, PR, Brazil
- Little Prince College, Curitiba, PR, Brazil
| | - Pedro De Marchi
- Department of Medical Oncology, Barretos Cancer Hospital, Barretos, SP, Brazil
- Oncoclinicas, Rio de Janeiro, RJ, Brazil
| | - Neil Hayes
- Department of Medicine, Division of Oncology, UTHSC Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - André Lopes Carvalho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.
- International Agency of Research on Cancer, Lyon, France.
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13
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Kostrzewska-Poczekaj M, Bednarek K, Jarmuz-Szymczak M, Bodnar M, Filas V, Marszalek A, Bartochowska A, Grenman R, Kiwerska K, Szyfter K, Giefing M. Copy number gains of the putative CRKL oncogene in laryngeal squamous cell carcinoma result in strong nuclear expression of the protein and influence cell proliferation and migration. Sci Rep 2020; 10:24. [PMID: 31913340 PMCID: PMC6949282 DOI: 10.1038/s41598-019-56870-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 12/10/2019] [Indexed: 02/03/2023] Open
Abstract
Laryngeal squamous cell carcinoma is a major medical problem worldwide. Although our understanding of genetic changes and their consequences in laryngeal cancer has opened new therapeutic pathways over the years, the diagnostic as well as treatment options still need to be improved. In our previous study, we identified CRKL (22q11) as a novel putative oncogene overexpressed and amplified in a subset of LSCC tumors and cell lines. Here we analyze to what extent CRKL DNA copy number gains correlate with the higher expression of CRKL protein by performing IHC staining of the respective protein in LSCC cell lines (n = 3) and primary tumors (n = 40). Moreover, the importance of CRKL gene in regard to proliferation and motility of LSCC cells was analyzed with the application of RNA interference (siRNA). Beside the physiological cytoplasmic expression, the analysis of LSCC tumor samples revealed also nuclear expression of CRKL protein in 10/40 (25%) cases, of which three (7.5%), presented moderate or strong nuclear expression. Similarly, we observed a shift towards aberrantly strong nuclear abundance of the CRKL protein in LSCC cell lines with gene copy number amplifications. Moreover, siRNA mediated silencing of CRKL gene in the cell lines showing its overexpression, significantly reduced proliferation (p < 0.01) as well as cell migration (p < 0.05) rates. Altogether, these results show that the aberrantly strong nuclear localization of CRKL is a seldom but recurrent phenomenon in LSCC resulting from the increased DNA copy number and overexpression of the gene. Moreover, functional analyses suggest that proliferation and migration of the tumor cells depend on CRKL expression.
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Affiliation(s)
| | - Kinga Bednarek
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Malgorzata Jarmuz-Szymczak
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.,Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland
| | - Magdalena Bodnar
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.,Department of Otolaryngology and Laryngological Oncology, University of Medical Sciences, Poznan, Poland
| | - Violeta Filas
- Department of Oncologic Pathology and Prophylaxis, Poznan University of Medical Sciences & Greater Poland Cancer Center, Poznan, Poland
| | - Andrzej Marszalek
- Department of Oncologic Pathology and Prophylaxis, Poznan University of Medical Sciences & Greater Poland Cancer Center, Poznan, Poland
| | - Anna Bartochowska
- Department of Otolaryngology and Laryngological Oncology, University of Medical Sciences, Poznan, Poland
| | - Reidar Grenman
- Department of Otorhinolaryngology, Head and Neck Surgery, Turku University Central Hospital and Turku University, Turku, Finland
| | - Katarzyna Kiwerska
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.,Department of Tumor Pathology, Greater Poland Cancer Center, Poznan, Poland
| | - Krzysztof Szyfter
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Maciej Giefing
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
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14
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Choonoo G, Blucher AS, Higgins S, Boardman M, Jeng S, Zheng C, Jacobs J, Anderson A, Chamberlin S, Evans N, Vigoda M, Cordier B, Tyner JW, Kulesz-Martin M, McWeeney SK, Laderas T. Illuminating biological pathways for drug targeting in head and neck squamous cell carcinoma. PLoS One 2019; 14:e0223639. [PMID: 31596908 PMCID: PMC6785123 DOI: 10.1371/journal.pone.0223639] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 09/25/2019] [Indexed: 11/18/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either “light” or “dark” to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35–38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.
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Affiliation(s)
- Gabrielle Choonoo
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Aurora S. Blucher
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- * E-mail:
| | - Samuel Higgins
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Mitzi Boardman
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Sophia Jeng
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Christina Zheng
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - James Jacobs
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
- Pediatric Hematology and Oncology, OHSU Doernbecher Children’s Hospital, Portland, Oregon, United States of America
| | - Ashley Anderson
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Steven Chamberlin
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Nathaniel Evans
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Myles Vigoda
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Benjamin Cordier
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Jeffrey W. Tyner
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Molly Kulesz-Martin
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Shannon K. McWeeney
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
- Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Ted Laderas
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
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15
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Current Prospects of Molecular Therapeutics in Head and Neck Squamous Cell Carcinoma. Pharmaceut Med 2019; 33:269-289. [DOI: 10.1007/s40290-019-00288-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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16
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Cen WN, Pang JS, Huang JC, Hou JY, Bao WG, He RQ, Ma J, Peng ZG, Hu XH, Ma FC. The expression and biological information analysis of miR-375-3p in head and neck squamous cell carcinoma based on 1825 samples from GEO, TCGA, and peer-reviewed publications. Pathol Res Pract 2018; 214:1835-1847. [PMID: 30243807 DOI: 10.1016/j.prp.2018.09.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 08/26/2018] [Accepted: 09/11/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The specific expression level and clinical significance of miR-375-3p in HNSCC had not been fully stated, as well as the overall biological function and molecular mechanisms. Therefore, we purpose to carry out a comprehensive meta-analysis to further explore the clinical significance and potential function mechanism of miR-375-3p in HNSCC. METHODS HNSCC-related data was gained from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and peer-reviewed journals. A meta-analysis was carried out to comprehensively explore the relationship between miR-375-3p expression level and clinicopathological features of HNSCC. And summary receiver operating characteristic (SROC) curve analysis was applied for evaluating disease diagnosis value of miR-375-3p. In addition, a biological pathway analysis was also performed to assess the possible molecular mechanism of miR-375-3p in HNSCC. RESULTS A total of 24 available records and references were added into analysis. The overall pooled meta-analysis outcome revealed a relatively lower expression level of miR-375-3p in HNSCC specimens than that in non-cancerous controls (P < 0.001). And SROC curve analysis showed that the pooled area under the SROC curve (AUC) was 0.90 (95%CI: 0.88-0.93). In addition, biological pathway analysis indicated that LAMC1, EDIL3, FN1, VEGFA, IGF2BP2, and IGF2BP3 maybe the latent target genes of miR-375-3p, which were greatly enriched in the pathways of beta3 integrin cell surface interactions and the binding of RNA via the insulin-like growth factor-2 mRNA-binding protein (IGF2BPs/IMPs/VICKZs). CONCLUSION MiR-375-3p expression clearly decreased in HNSCC samples compared with non-cancerous controls. Meanwhile, miR-375-3p may serve as a tumor suppressor via regulating tumor-related genes LAMC1, EDIL3, FN1, VEGFA, IGF2BP2, and IGF2BP3 in HNSCC.
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Affiliation(s)
- Wei-Ning Cen
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Jin-Shu Pang
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Jia-Cheng Huang
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Jia-Yin Hou
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Wen-Guang Bao
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Rong-Quan He
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Jie Ma
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Zhi-Gang Peng
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Xiao-Hua Hu
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Fu-Chao Ma
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China.
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