The Cancer Genome Atlas (TCGA) conducted a comprehensive genomic analysis of 279 head and neck squamous cell carcinomas (HNSCCs), revealing key genetic alterations. HPV-associated tumors showed mutations in PIK3CA, loss of TRAF3, and amplification of E2F1, while smoking-related tumors had TP53 and CDKN2A mutations. A subgroup of oral cavity tumors had rare copy number alterations and activating mutations in HRAS or PIK3CA, along with inactivating mutations in CASP8, NOTCH1, and TP53. Other subgroups had alterations in NSD1, WNT pathway genes, and NFE2L2. Therapeutic targets were identified in most HNSCCs. HNSCCs affect around 600,000 patients annually, with significant heterogeneity. Smoking is a major risk factor in developing countries, while HPV is increasingly linked to oropharyngeal cancers in developed countries. Despite treatment, about half of patients die from the disease. Risk stratification is based on anatomic site, stage, and histological features. HPV status is a key factor, but other molecular and clinical factors have limited clinical utility. Genomic profiling of HNSCCs has been limited to single platforms. TCGA used a multi-platform approach to characterize 500 tumors, identifying somatic variants in at least 5% of samples. The study included 279 patients with complete data, primarily from the oral cavity, oropharynx, and larynx. Most patients were male and heavy smokers. HPV status was determined by RNA-Seq reads, with 36 HPV(+) and 243 HPV(−) tumors. HPV(+) tumors had infrequent TP53 mutations and CDKN2A inactivation, while HPV(−) tumors had frequent 11q13/22 amplifications. DNA and RNA structural alterations were common, with copy number alterations resembling lung squamous cell carcinomas. HPV(+) tumors had novel deletions and truncating mutations in TRAF3, which is involved in antiviral responses. HPV(−) tumors had co-amplifications of 11q13 and 11q22, and focal deletions in NSD1 and other tumor suppressor genes. Recurrent focal amplifications in receptor tyrosine kinases were also observed in HPV(−) tumors. Somatic mutations were identified, with TP53, CDKN2A, FAT1, and AJUBA being frequently mutated. HPV(+) tumors had infrequent TP53 mutations, while HPV(−) tumors had frequent TP53 mutations. Mutations in HRAS, CASP8, and TP53 were associated with favorable outcomes. The study identified several therapeutic targets, including PIK3CA, HRAS, and CASPThe Cancer Genome Atlas (TCGA) conducted a comprehensive genomic analysis of 279 head and neck squamous cell carcinomas (HNSCCs), revealing key genetic alterations. HPV-associated tumors showed mutations in PIK3CA, loss of TRAF3, and amplification of E2F1, while smoking-related tumors had TP53 and CDKN2A mutations. A subgroup of oral cavity tumors had rare copy number alterations and activating mutations in HRAS or PIK3CA, along with inactivating mutations in CASP8, NOTCH1, and TP53. Other subgroups had alterations in NSD1, WNT pathway genes, and NFE2L2. Therapeutic targets were identified in most HNSCCs. HNSCCs affect around 600,000 patients annually, with significant heterogeneity. Smoking is a major risk factor in developing countries, while HPV is increasingly linked to oropharyngeal cancers in developed countries. Despite treatment, about half of patients die from the disease. Risk stratification is based on anatomic site, stage, and histological features. HPV status is a key factor, but other molecular and clinical factors have limited clinical utility. Genomic profiling of HNSCCs has been limited to single platforms. TCGA used a multi-platform approach to characterize 500 tumors, identifying somatic variants in at least 5% of samples. The study included 279 patients with complete data, primarily from the oral cavity, oropharynx, and larynx. Most patients were male and heavy smokers. HPV status was determined by RNA-Seq reads, with 36 HPV(+) and 243 HPV(−) tumors. HPV(+) tumors had infrequent TP53 mutations and CDKN2A inactivation, while HPV(−) tumors had frequent 11q13/22 amplifications. DNA and RNA structural alterations were common, with copy number alterations resembling lung squamous cell carcinomas. HPV(+) tumors had novel deletions and truncating mutations in TRAF3, which is involved in antiviral responses. HPV(−) tumors had co-amplifications of 11q13 and 11q22, and focal deletions in NSD1 and other tumor suppressor genes. Recurrent focal amplifications in receptor tyrosine kinases were also observed in HPV(−) tumors. Somatic mutations were identified, with TP53, CDKN2A, FAT1, and AJUBA being frequently mutated. HPV(+) tumors had infrequent TP53 mutations, while HPV(−) tumors had frequent TP53 mutations. Mutations in HRAS, CASP8, and TP53 were associated with favorable outcomes. The study identified several therapeutic targets, including PIK3CA, HRAS, and CASP