Journal Article

Comprehensive genomic characterization of head and neck squamous cell carcinomas

Lawrence, Michael S, Sougnez, Carrie, Lander, Eric, Cibulskis, Kristian, Gabriel, Stacey B, Getz, Gad, Lichtenstein, Lee

2015

Overview

The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA , novel alterations involving loss of TRAF3 , and amplification of the cell cycle gene E2F1 . Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA , coupled with inactivating mutations of CASP8 , NOTCH1 and TP53 . Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1 , WNT pathway genes AJUBA and FAT1 , and activation of oxidative stress factor NFE2L2 , mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs. The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR , FGFR , PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs. Large-scale analysis of head and neck cancers Squamous cell head and neck cancer is one of the most common and deadly cancers. Despite initial responses to combinations of surgery, radiation and chemotherapy, approximately half of all tumours recur, usually within two years of initial diagnosis. Molecular markers and targeted therapies have had little impact on this disease to date. Here, The Cancer Genome Atlas team presents a detailed genome-wide overview of alterations and highlights critical genetic events of potential biological and clinical significance in head and neck squamous cell carcinomas (HNSCCs) with different human papillomavirus status. Mutational profiles reveal distinct subgroups of HNSCCs. Mutations in EGFR, FGFRs, PIK3CA and cyclin-dependent kinases represent candidate targets for therapeutic intervention in the majority of HNSCCs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/23 / 45/91 / 692/699 / 692/699/67/1536 / Apoptosis / Cancer / Cancer therapies / Carcinoma, Squamous Cell - genetics / Cell cycle / Chemical properties / DNA Copy Number Variations - genetics / DNA methylation / DNA, Neoplasm - genetics / Female / Gene expression / Gene Expression Regulation, Neoplastic - genetics / Genetic aspects / Genetic research / Genome, Human - genetics / Genomes / Genomics / Head & neck cancer / Head and neck cancer / Head and Neck Neoplasms - genetics / Humanities and Social Sciences / Humans / Inactivation / Kinases / Male / Molecular Targeted Therapy / multidisciplinary / Mutation / Mutation - genetics / Oncogenes - genetics / Oncology, Experimental / Oxidative stress / Papillomavirus infections / RNA, Neoplasm - genetics / Science / Signal Transduction - genetics / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck / Transcription factors / Transcription Factors - metabolism / Tumors