This study compares the somatic genome alterations in lung adenocarcinomas (ADC) and lung squamous cell carcinomas (SqCC) using exome sequencing and copy number profiles of 660 ADC and 484 SqCC tumor/normal pairs. The results show that recurrent alterations in SqCCs are more similar to other squamous carcinomas than to ADCs. Novel significantly mutated genes include PPP3CA, DOT1L, and FTSJD1 in ADC, RASA1 in SqCC, and KLF5, EP300, and CREBBP in both. Amplification peaks include MIR21 in ADC, MIR205 in SqCC, and MAPK1 in both. ADCs lacking receptor tyrosine kinase/Ras/Raf alterations showed mutations in SOS1, VAV1, RASA1, and ARHGAP35. Neoantigen analysis revealed that 47% of ADCs and 53% of SqCCs had at least 5 predicted neoepitopes. While targeted therapies for ADC and SqCC are distinct, immunotherapies may benefit both subtypes. The study also identified mutational signatures in lung cancer, including UV-related, smoking-related, mismatch repair, and APOBEC-related signatures. These signatures were associated with different mutational patterns and tumor characteristics. Novel significantly mutated genes in ADC included STK11, RBM10, KEAP1, RAF1, RIT1, and MET. In SqCC, genes like NFE2L2, KDM6A, RASA1, NOTCH1, and HRAS were significantly mutated. Genes involved in epigenetic regulation or immune-related pathways were also identified. Novel somatic copy number alterations included focal amplifications and deletions, with specific genes like NKX2-1, MYC, TERT, MCL1, and MDM2 in ADC, and SOX2, CCND1, WHSC1L1/FGFR1, MYC, and EGFR in SqCC. The study also identified Ras/Raf/RTK drivers in ADC, including SOS1, RASA1, VAV1, and ARHGAP35. These genes were enriched for loss-of-function mutations. Additionally, oncogene-negative ADCs showed significant alterations in known or putative Ras/Raf/RTK driver genes. The study found that 499 (76%) of ADCs had alterations in known or putative Ras/Raf/RTK driver genes. The analysis of neoantigen load and recurrence revealed that 47% of ADCs and 53% of SqCCs had at least 5 predicted neoepitopes, suggesting potential for immunotherapy. The study highlights the distinct somatic alterations between ADC and SqCC, with ADCs showing more similarity to glioblastThis study compares the somatic genome alterations in lung adenocarcinomas (ADC) and lung squamous cell carcinomas (SqCC) using exome sequencing and copy number profiles of 660 ADC and 484 SqCC tumor/normal pairs. The results show that recurrent alterations in SqCCs are more similar to other squamous carcinomas than to ADCs. Novel significantly mutated genes include PPP3CA, DOT1L, and FTSJD1 in ADC, RASA1 in SqCC, and KLF5, EP300, and CREBBP in both. Amplification peaks include MIR21 in ADC, MIR205 in SqCC, and MAPK1 in both. ADCs lacking receptor tyrosine kinase/Ras/Raf alterations showed mutations in SOS1, VAV1, RASA1, and ARHGAP35. Neoantigen analysis revealed that 47% of ADCs and 53% of SqCCs had at least 5 predicted neoepitopes. While targeted therapies for ADC and SqCC are distinct, immunotherapies may benefit both subtypes. The study also identified mutational signatures in lung cancer, including UV-related, smoking-related, mismatch repair, and APOBEC-related signatures. These signatures were associated with different mutational patterns and tumor characteristics. Novel significantly mutated genes in ADC included STK11, RBM10, KEAP1, RAF1, RIT1, and MET. In SqCC, genes like NFE2L2, KDM6A, RASA1, NOTCH1, and HRAS were significantly mutated. Genes involved in epigenetic regulation or immune-related pathways were also identified. Novel somatic copy number alterations included focal amplifications and deletions, with specific genes like NKX2-1, MYC, TERT, MCL1, and MDM2 in ADC, and SOX2, CCND1, WHSC1L1/FGFR1, MYC, and EGFR in SqCC. The study also identified Ras/Raf/RTK drivers in ADC, including SOS1, RASA1, VAV1, and ARHGAP35. These genes were enriched for loss-of-function mutations. Additionally, oncogene-negative ADCs showed significant alterations in known or putative Ras/Raf/RTK driver genes. The study found that 499 (76%) of ADCs had alterations in known or putative Ras/Raf/RTK driver genes. The analysis of neoantigen load and recurrence revealed that 47% of ADCs and 53% of SqCCs had at least 5 predicted neoepitopes, suggesting potential for immunotherapy. The study highlights the distinct somatic alterations between ADC and SqCC, with ADCs showing more similarity to glioblast