title: The FA/BRCA Pathway Identified as the Major Predictor of Cisplatin Response in Head and Neck Cancer by Functional Genomics.
abstract: Patients with advanced stage head and neck squamous cell carcinoma (HNSCC) are often treated with cisplatin-containing chemoradiation protocols. Although cisplatin is an effective radiation sensitizer, it causes severe toxicity and not all patients benefit from the combination treatment. HNSCCs expectedly not responding to cisplatin may better be treated with surgery and postoperative radiation or cetuximab and radiation, but biomarkers to personalize chemoradiotherapy are not available. We performed an unbiased genome-wide functional genetic screenin vitroto identify genes that influence the response to cisplatin in HNSCC cells. By siRNA-mediated knockdown, we identified the Fanconi anemia/BRCA pathway as the predominant pathway for cisplatin response in HNSCC cells. We also identified the involvement of theSHFM1gene in the process of DNA cross-link repair. Furthermore, expression profiles based on these genes predict the prognosis of radiation- and chemoradiation-treated head and neck cancer patients. This genome-wide functional analysis designated the genes that are important in the response of HNSCC to cisplatin and may guide further biomarker validation. Cisplatin imaging as well as biomarkers that indicate the activity of the Fanconi anemia/BRCA pathway in the tumors are the prime candidates.Mol Cancer Ther; 16(3); 540-50. ©2016 AACR.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Sanne R
authors.initials: SR
authors.lastname: Martens-de Kemp
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Brink
authors.affiliation: RNA Interference Functional Oncogenomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Ida H
authors.initials: IH
authors.lastname: van der Meulen
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Renée X
authors.initials: RX
authors.lastname: de Menezes
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Te Beest
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: C René
authors.initials: CR
authors.lastname: Leemans
authors.affiliation: RNA Interference Functional Oncogenomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Victor W
authors.initials: VW
authors.lastname: van Beusechem
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Boudewijn J M
authors.initials: BJ
authors.lastname: Braakhuis
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands. rh.brakenhoff@vumc.nl.
authors.forename: Ruud H
authors.initials: RH
authors.lastname: Brakenhoff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000970:Antineoplastic Agents; D051856:Fanconi Anemia Complementation Group Proteins; D034741:RNA, Small Interfering; D002945:Cisplatin