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

TL;DR: The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes, includingtargetable genomic alterations in FGFR1, DDR2, EGFR, FGFR2/3, EPHA2, and PIK3CA.

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 (425% 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 152 versus 144 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 176% 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 58% incidence of KRAS mutations, and DNA-repair gene aberrations, including 78% 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 Clin Cancer Res; 21(3); 632–41 ©2014 AACR See related commentary by Krigsfeld and Chung, p 495