Somatic alterations in TP53 , PIK3CA , and CCND1 reveal exposure-driven patterns in oral and oropharyngeal tumors
Year: 2026
Type: article
Study design: Observational Study
Abstract: Tobacco, alcohol, and human papillomavirus (HPV) are major risk factors for oral cavity (OC) and oropharyngeal (OPC) cancers, yet their specific contributions to the tumor molecular landscape remain incompletely understood. We analyzed somatic alterations in 1,086 tumors (606 OC, 480 OPC, including 287 HPV(+)OPC) profiled with a 1,109-gene panel and evaluated their associations with exposures. PIK3CA alterations were widespread but context-specific: HPV(+)OPC featured APOBEC-driven mutations and co-occurrence of FGFR3 mutations in a subset of cases, while HPV(-)OPC and OC were marked by 3q26/28 (PIK3CA/TP63/SOX2) amplifications. TP53 was the most frequently mutated gene in HPV(-) tumors, with strong enrichment among smokers in HPV(-)OPC, whereas TP53 mutation frequencies in OC were consistently high regardless of smoking status. CCND1 amplifications were largely restricted to HPV(-) tumors and were most frequent in individuals reporting combined tobacco/alcohol use. This combined effect was replicated in the TCGA OC-OPC cohort and mirrored at the transcriptomic level, where CCND1 mRNA expression was highest in dual users. Within OC, characterization of one of the largest cohorts of tumors from never smoker-never drinkers to date (N = 100) showed they were more likely to be from female patients and to exhibit enrichment for FAT1 and CASP8 mutations compared to tumors from ever smoker-ever drinkers (N = 353). Together, these findings define distinct, exposure-driven patterns of somatic alterations by subsite and HPV status, and provide a molecular framework that may inform etiologic-based risk stratification in head and neck cancer.
DOI: 10.1093/jnci/djag267
Authors: Ricardo Cortez Cardoso Penha, Shama Virani, Jeremiah R Holt, Xiaobei Zhao, Paul Little, Myriam Brossard, Valérie Gaborieau, Maja Milojevic, Laura Torrens, Hanla A Park, Tom Dudding, Wendell G Yarbrough, Miranda Pring, Vonn Walter, Scott V Bratman, Wolfgang Ahrens, Laia Alemany, Cristina Canova, David I Conway, Claire M Healy, Ivana Holcatova, Luis Felipe Ribeiro Pinto, Maria Paula Curado, Sandra Ventorin von Zeidler, Jose Carlos de Oliveira, José Roberto Vasconcelos de Podestá, Marta Vilensky, Areti Lagiou, Gary J Macfarlane, Jerry Polesel, Lorenzo Richiardi, Max Robinson, Ariana Znaor, Jose Zevallos, Sandra Perdomo, Paul Brennan, Rayjean J Hung, Tim Waterboer, Geoffrey Liu, Andrew F Olshan, Brenda Diergaarde, David Neil Hayes, James D McKay
Institutions: Centre international de recherche sur le cancer, University of Tennessee Health Science Center, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Copenhagen University Hospital, Rigshospitalet, Centre of Excellence for Health, Immunity and Infections, University of Bristol, University of North Carolina at Chapel Hill, Pennsylvania State University, University of Toronto, Princess Margaret Cancer Centre, Leibniz Institute for Prevention Research and Epidemiology - BIPS, Institut Català d'Oncologia, University of Padua, University of Glasgow, Trinity College Dublin, Dublin Dental University Hospital, Charles University, University Hospital in Motol, Instituto Nacional de Câncer - INCA, AC Camargo Hospital, Universidade Federal do Espírito Santo, Hospital Araújo Jorge, Universidad de Buenos Aires, University of West Attica, University of Aberdeen, Centro di Riferimento Oncologico, University of Turin, Newcastle upon Tyne Hospitals NHS Foundation Trust, University of Pittsburgh Medical Center, German Cancer Research Center, University of Pittsburgh, UPMC Hillman Cancer Center
Language: English
Topic: Head and Neck Cancer Studies
Subfield: Otorhinolaryngology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,436
Funders: Compagnia di San Paolo, University of Pittsburgh, National Institute for Health and Care Research, European Commission, Fundação de Amparo à Pesquisa e Inovação do Espírito Santo, National Institutes of Health, Canadian Cancer Society Research Institute, Programme Grants for Applied Research, National Cancer Institute, National Institute of Dental and Craniofacial Research
Awards: Germline risk of oral and oropharyngeal cancers across diverse populations, G1276524703, G2642749895, G4444790347, Gene Environment Interaction in Head and Neck Cancer, The role of germline and somatic DNA mutations in oral and oropharyngeal cancers, Evidence based health care for major congenital and acquired problems of the head and neck, G633032242, G6966134840, G8247575195, Head and Neck Cancer SPORE, Cancer Center Support Grant
OpenAlex ID: W7202363081