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Background: Head and neck squamous cell carcinoma(HNSCC)is a leading cause of cancer death in worldwide.Methods: The Cancer Genome Atlas(TCGA)is conducting DNA,RNA and miRNA sequencing along with DNA copy number profiling,quantification of mRNA expression,promoter methylation,and reverse-phase protein arrays on surgically resected samples from previously untreated patients with HNSCC.We report for the first time the integrated genomic alterations for 279 HNSCC patients.Results: The demographics of 279 patients enrolled in the study show a median age of 61 years(range: 19-90); 27%female,and history of tobacco smoking in 80%.Over 30 sites of significant somatic copy number alteration were identified as well as 15 significantly mutated genes at the false fiscovery rate of <0.01,including: CDKN2A,TP53,PIK3CA,FAT1,MLL2,TGFBR2,HLA-A,NOTCH1,HRAS,NFE2L2,and CASP8.Evidence of the human papilloma virus(HPV)was observed by sequencing in up to 25%of samples.Integrated genomics data supported expected patterns including the predominant role of HPV type 16 infection in nonsmoking patients with tumors of the oropharynx which are wild-type for the tumor suppressor genes p16,Rb,and p53.In addition,striking atypical cases and viral infections will be presented as well as novel anti-correlation of HPV infection with focal copy number alterations including EGFR amplification and chromosome 11q.By contrast co-occurrence of HPV with focal deletions of TRAF3 and mutations of the oncogene PIK3CA will be described.Integrated tumor subtypes defined by gene expression,methylation,and miRNA will be presented in conjunction with associated mutations exclusive to tumor subtypes.For example,alterations of the “antioxidant response elements” transcription activators NFE2L2 and KEAP1 will be documented in association with the “classical” expression subtype of HNSCC,as has been shown in lung squamous cell carcinoma.By contrast,co-occurrence of CASP8 and HRAS will be documented in the “Basal” subtype.Conclusions: While,HNSCC is a heterogeneous tumor,coordinated tumor alterations are observed,including potentially targetable genes and pathways.Results presented on behalf of TCGA.