Integrative and Comparative Genomic Analysis of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas

被引:498
作者
Seiwert, Tanguy Y. [1 ,2 ,3 ]
Zuo, Zhixiang [1 ]
Keck, Michaela K. [1 ]
Khattri, Arun [1 ]
Pedamallu, Chandra S. [4 ,5 ]
Stricker, Thomas [6 ]
Brown, Christopher [7 ]
Pugh, Trevor J. [4 ,5 ]
Stojanov, Petar [4 ]
Cho, Juok [4 ]
Lawrence, Michael S. [4 ]
Getz, Gad [4 ]
Braegelmann, Johannes [1 ]
DeBoer, Rebecca [1 ]
Weichselbaum, Ralph R. [2 ,8 ]
Langerman, Alexander [2 ,9 ]
Portugal, Louis [2 ,9 ]
Blair, Elizabeth [2 ,9 ]
Stenson, Kerstin [2 ,9 ]
Lingen, Mark W. [2 ,10 ]
Cohen, Ezra E. W. [1 ,2 ]
Vokes, Everett E. [1 ,2 ]
White, Kevin P. [2 ,3 ]
Hammerman, Peter S. [4 ,5 ]
机构
[1] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA
[2] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA
[3] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA
[4] Broad Inst Harvard & MIT, Cambridge, MA USA
[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[6] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Nashville, TN 37235 USA
[7] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA
[8] Univ Chicago, Dept Radiat Oncol, Chicago, IL 60637 USA
[9] Univ Chicago, Dept Otolaryngol Head & Neck Surg, Chicago, IL 60637 USA
[10] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
关键词
HUMAN-PAPILLOMAVIRUS; COPY-NUMBER; MUTATIONAL LANDSCAPE; FREQUENT MUTATION; CANCER; FGFR3; FLUOROURACIL; CISPLATIN; RECURRENT; PATHWAY;
D O I
10.1158/1078-0432.CCR-13-3310
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (C) 2014 AACR.
引用
收藏
页码:632 / 641
页数:10
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