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Clin Cancer Res DOI:10.1158/1078-0432.CCR-13-3310

Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas.

Publication TypeJournal Article
Year of Publication2015
AuthorsSeiwert, TY, Zuo, Z, Keck, MK, Khattri, A, Pedamallu, CS, Stricker, T, Brown, C, Pugh, TJ, Stojanov, P, Cho, J, Lawrence, MS, Getz, G, Brägelmann, J, DeBoer, R, Weichselbaum, RR, Langerman, A, Portugal, L, Blair, E, Stenson, K, Lingen, MW, Cohen, EEW, Vokes, EE, White, KP, Hammerman, PS
JournalClin Cancer Res
Volume21
Issue3
Pages632-41
Date Published2015 Feb 01
ISSN1078-0432
KeywordsAdult, Aged, Carcinoma, Squamous Cell, Cohort Studies, DNA Copy Number Variations, Female, Gene Expression Profiling, Genomics, Head and Neck Neoplasms, Human papillomavirus 16, Human papillomavirus 18, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Papillomaviridae, Papillomavirus Infections, Prognosis, Protein Interaction Maps, Risk Factors, Signal Transduction, Tumor Virus Infections
Abstract

PURPOSE: The genetic differences between human papilloma virus (HPV)-positive and -negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown. To identify differential biology and novel therapeutic targets for both entities, we determined mutations and copy-number aberrations in a large cohort of locoregionally advanced HNSCC.

EXPERIMENTAL DESIGN: We performed massively parallel sequencing of 617 cancer-associated genes in 120 matched tumor/normal samples (42.5% HPV-positive). Mutations and copy-number aberrations were determined and results validated with a secondary method.

RESULTS: The overall mutational burden in HPV-negative and HPV-positive HNSCC was similar with an average of 15.2 versus 14.4 somatic exonic mutations in the targeted cancer-associated genes. HPV-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, PIK3CA, and NOTCH genes. HPV-positive tumors showed unique mutations in DDX3X, FGFR2/3 and aberrations in PIK3CA, KRAS, MLL2/3, and NOTCH1 were enriched in HPV-positive tumors. Currently targetable genomic alterations were identified in FGFR1, DDR2, EGFR, FGFR2/3, EPHA2, and PIK3CA. EGFR, CCND1, and FGFR1 amplifications occurred in HPV-negative tumors, whereas 17.6% of HPV-positive tumors harbored mutations in fibroblast growth factor receptor genes (FGFR2/3), including six recurrent FGFR3 S249C mutations. HPV-positive tumors showed a 5.8% incidence of KRAS mutations, and DNA-repair gene aberrations, including 7.8% BRCA1/2 mutations, were identified.

CONCLUSIONS: The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes. HNSCC harbors multiple therapeutically important genetic aberrations, including frequent aberrations in the FGFR and PI3K pathway genes. See related commentary by Krigsfeld and Chung, p. 495.

URLhttp://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=25056374
DOI10.1158/1078-0432.CCR-13-3310
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25056374?dopt=Abstract

Alternate JournalClin. Cancer Res.
PubMed ID25056374
PubMed Central IDPMC4305034
Grant ListK08 CA163677 / CA / NCI NIH HHS / United States
UL1 TR000430 / TR / NCATS NIH HHS / United States
1K08CA163677 / CA / NCI NIH HHS / United States