A comprehensive molecular profile of 230 resected lung adenocarcinomas was conducted using integrated analysis of messenger RNA, microRNA, and DNA sequencing, along with copy number, methylation, and proteomic data. The study identified a high rate of somatic mutations, with 8.9 mutations per megabase. Eighteen genes were found to be significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations, which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, while RBM10 mutations were more common in males. Aberrations in NF1, MET, ERBB2, and RIT1 occurred in 13% of cases and were enriched in samples lacking an activated oncogene, suggesting a driver role for these events. DNA and mRNA sequence data from the same tumor highlighted splicing alterations driven by somatic genomic changes, including MET exon 14 skipping in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis. Lung cancer is the most common cause of global cancer-related mortality, leading to over a million deaths each year, with adenocarcinoma being the most common histological type. Smoking is the major cause of lung adenocarcinoma, but as smoking rates decrease, proportionally more cases occur in never-smokers. Molecularly targeted therapies have improved treatment for patients with tumors harboring somatically activated oncogenes such as mutant EGFR or translocated ALK, RET, or ROS1. However, most lung adenocarcinomas either lack an identifiable driver oncogene or harbor mutations in KRAS and are still treated with conventional chemotherapy. Tumor suppressor gene abnormalities, such as those in TP53, STK11, CDKN2A, KEAP1, and SMARCA4, are also common but not currently clinically actionable. Lung adenocarcinoma shows high rates of somatic mutation and genomic rearrangement, challenging identification of all but the most frequent driver gene alterations. The study identified 18 statistically significant mutated genes, including TP53, KRAS, EGFR, BRAF, PIK3CA, MET, RIT1, STK11, KEAP1, NF1, RB1, CDKN2A, SETD2, ARID1A, SMARCA4, RBM10, and U2AF1. Mutations in the MGA gene, which encodes a Max-interacting protein on the MYC pathway, occurred in 8% of samples. Loss-of-function mutations in MGA were mutually exclusive with focalA comprehensive molecular profile of 230 resected lung adenocarcinomas was conducted using integrated analysis of messenger RNA, microRNA, and DNA sequencing, along with copy number, methylation, and proteomic data. The study identified a high rate of somatic mutations, with 8.9 mutations per megabase. Eighteen genes were found to be significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations, which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, while RBM10 mutations were more common in males. Aberrations in NF1, MET, ERBB2, and RIT1 occurred in 13% of cases and were enriched in samples lacking an activated oncogene, suggesting a driver role for these events. DNA and mRNA sequence data from the same tumor highlighted splicing alterations driven by somatic genomic changes, including MET exon 14 skipping in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis. Lung cancer is the most common cause of global cancer-related mortality, leading to over a million deaths each year, with adenocarcinoma being the most common histological type. Smoking is the major cause of lung adenocarcinoma, but as smoking rates decrease, proportionally more cases occur in never-smokers. Molecularly targeted therapies have improved treatment for patients with tumors harboring somatically activated oncogenes such as mutant EGFR or translocated ALK, RET, or ROS1. However, most lung adenocarcinomas either lack an identifiable driver oncogene or harbor mutations in KRAS and are still treated with conventional chemotherapy. Tumor suppressor gene abnormalities, such as those in TP53, STK11, CDKN2A, KEAP1, and SMARCA4, are also common but not currently clinically actionable. Lung adenocarcinoma shows high rates of somatic mutation and genomic rearrangement, challenging identification of all but the most frequent driver gene alterations. The study identified 18 statistically significant mutated genes, including TP53, KRAS, EGFR, BRAF, PIK3CA, MET, RIT1, STK11, KEAP1, NF1, RB1, CDKN2A, SETD2, ARID1A, SMARCA4, RBM10, and U2AF1. Mutations in the MGA gene, which encodes a Max-interacting protein on the MYC pathway, occurred in 8% of samples. Loss-of-function mutations in MGA were mutually exclusive with focal