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

Integrative and Comparative Genomic Analysis of HPV-Positive...

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中国生物工程学会第六次全国会员代表大会暨第九届学术年会

作者： 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 Br?gelmann Rebecca DeBoer Ralph R.Weichselbaum Alexander Langerman Louis Portugal Elizabeth Blair kerstin stenson Mark W.Lingen Ezra E.W.Cohen Everett E.Vokes Kevin P.White Peter S.Hammerman Section of Hematology/Oncology Department of MedicineThe University of Chicago The University of Chicago Comprehensive Cancer Center Institute for Genomics and Systems Biology University of Chicago Broad Institute of Harvard and MIT Department of Medical Oncology Dana Farber Cancer Institute Department of Pathology Microbiologyand ImmunologyVanderbilt University Department of Genetics University of Pennsylvania Department of Radiation Oncology The University of Chicago Department of Otolaryngology/Head and Neck Surgery The University of Chicago Department of Pathology University of Chicago

Purpose:The genetic differences between human papilloma virus(HPV)–positive and –negative head and neck squamous cell carcinomas(HNSCC) remain largely *** identify differential biology and novel therapeutic targets for both entities,we determined mutations and copy-number aberrations in a large cohort of locoregionally advanced *** 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 ***:The overall mutational burden in HPV-negative and HPV-positive HNSCC was similar with an average of 15.2 versus14.4 somatic exonic mutations in the targeted cancer-associated ***-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53,CDKN2 A,MLL2,CUL3,NSD1,PIK3 CA,and NOTCH ***-positive tumors showed unique mutations in DDX3 X,FGFR2/3 and aberrations in PIK3 CA,KRAS,MLL2/3,and NOTCH1 were enriched in HPVpositive *** targetable genomic alterations were identified in FGFR1,DDR2,EGFR,FGFR2/3,EPHA2,and PIK3 ***,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 S249 C ***-positive tumors showed a 5.8% incidence of KRAS mutations,and DNArepair gene aberrations,including 7.8% BRCA1/2 mutations,were ***:The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly,including targetable *** harbors multiple therapeutically important genetic aberrations,including frequent aberrations in the FGFR and PI3K pathway genes.

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