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

Tanguy Y. Seiwert, Zhixiang Zuo, Michaela K. Keck, Arun Khattri, Chandra S. Pedamallu, Thomas Stricker, Christopher Brown, Trevor J. Pugh, Petar Stojanov, Juok Cho, Michael S. Lawrence, Gad Getz, Johannes Brägelmann, Rebecca DeBoer, Ralph R. Weichselbaum, Alexander Langerman, Louis Portugal, Elizabeth Blair, Kerstin Stenson, Mark W. LingenEzra E.W. Cohen, Everett E. Vokes, Kevin P. White, Peter S. Hammerman

Research output: Contribution to journalArticlepeer-review

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 HPVpositive 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 DNArepair gene aberrations, including 7.8% BRCA1/2 mutations, were identified. Conclusions: The mutational makeup of HPV-positive and HPV-negative HNSCC differs signi ficantly, including targetable genes. HNSCC harbors multiple therapeutically important genetic aberrations, including frequent aberrations in the FGFR and PI3K pathway genes.

Original languageEnglish (US)
Pages (from-to)632-641
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number3
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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