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. 2015 Feb 1;21(3):632-41.
doi: 10.1158/1078-0432.CCR-13-3310. Epub 2014 Jul 23.

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

Tanguy Y Seiwert  1 , Zhixiang Zuo  2 , Michaela K Keck  2 , Arun Khattri  2 , Chandra S Pedamallu  3 , Thomas Stricker  4 , Christopher Brown  5 , Trevor J Pugh  3 , Petar Stojanov  6 , Juok Cho  6 , Michael S Lawrence  6 , Gad Getz  6 , Johannes Brägelmann  2 , Rebecca DeBoer  2 , Ralph R Weichselbaum  7 , Alexander Langerman  8 , Louis Portugal  8 , Elizabeth Blair  8 , Kerstin Stenson  8 , Mark W Lingen  9 , Ezra E W Cohen  10 , Everett E Vokes  10 , Kevin P White  11 , Peter S Hammerman  3
Affiliations

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

Tanguy Y Seiwert et al. Clin Cancer Res. .

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.

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Conflict of interest statement

The authors report no conflict of interest.

Figures

Figure 1
Figure 1. Mutation events sorted by HPV status
(A) Left and right panel respectively: Left histogram: percentage of samples affected by an alteration in the corresponding gene on the right side, top histogram: number of mutations per megabase and sample, heat map:type of alteration events.(B) Copy number gains (red) and losses (blue) sorted by HPV status, samples are ordered by copy number events.
Figure 2
Figure 2. GISTIC-like copy number analysis derived from next generation sequencing data
Shown are the aberrant regions of the chromosome and the respective negative log2 of the q-value of the alteration in each panel, respectively. (A) Copy number gains in HPV(−) samples. (B) Copy number gains in HPV(+) samples. (C) Copy number losses in HPV(−) samples. (D) Copy number losses in HPV(+) samples.
Figure 3
Figure 3. Network based comparison of genetic aberrations in HPV-negative and HPV-positive tumors using protein-protein interaction (PPI) network prioritization (VarWalker) in order to identify significantly altered pathways/networks in each entity
The size of the symbols correlates with frequency of aberrations. M=non-synonymous mutation/s, A=amplification/s, D=deletion/s. Color choices are random, but are intended to highlight similarities and differences between HPV-positive and HPV-negative tumors. PPI connections are shown with grey lines, and connecting genes without genetic aberrations are shown with grey font.
Figure 4
Figure 4. Genomic alterations with translational or clinical relevance by HPV status
(A) Shown is the incidence of selected potentially targetable and their association with key pathways in HPV(−) and HPV(+) samples.(B) Gene diagrams for a selection of key mutations in potentially targetable genes, or presumed driver genes. Shown are the genes domains that are affected by somatic mutations, the number of cases that harbor the respective mutation is indicated on the ordinate axis, the CHASM scores and p-values for each mutation (red = <0.5 CHASM score, which indicates predicted oncogenic driver character), as well prior reports of mutations based on occurrence in COSMIC, or prior publications.
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