Background: Right-sided (RCC) and left-sided colon cancers (LCC) have different clinical/biological characteristics. Comprehensive genomic analysis (Whole exome/genome, Copy number, RNA, MicroRNA) using The Cancer Genome Atlas (TCGA) was performed to identify underlying genomic differences between RCRC, LCRC and rectal cancers (RC). Methods: 443 microsatellite stable RCC, LCC and RC samples were analyzed. Transverse and rectosigmoid tumors were excluded. MutsigCV and ConsensusDriver were used for significantly mutated gene analysis, GISTIC for copy number alterations (CNA), deSeq2 for RNA and microRNA analysis. Supervised clustering was applied to somatic mutations using Fuzzy ARTMAP. Results: AMER1 (gene in Wnt pathway) was mutated in 24% of RCC, 3% of LCC and 3% of RC. Mutations in AMER1 and other key Wnt family members (CTNNB1, GSK3, AXIN1, AXIN2, LRP5, LRP6) were mutually exclusive of each other. A novel driver B Melanoma Antigen Family, Member 2 (BAGE2) not previously described in CRC was discovered in a subset of samples using Fuzzy ARTMAP. KRAS, PIK3CA, SOX9 (all p < 0.05) mutations were enriched in RCC. New driver mutations in BCOR, MUC4, RELN, ROBO2, RP1L1, and MGAM were also enriched in RCC (all p < 0.05). Hotspot mutation analysis revealed distinct oncogenic mutations in RCC, including in APC (R1450*, p = 0.0246). We identified unique amplifications and deletions in RCC (1 amplification/10 deletions) and LCC (13 amplifications/10 deletions). Somatic mutation, CNA and hotspot analysis revealed similar changes in LCC and RC. RNA analysis revealed 53 genes differentially expressed between RCC and LCC and 73 genes between RCC and RC. The top upregulated and downregulated genes were common between the two groups (n = 32). INSL5 and PRAC1 are among the most downregulated genes while SLC10A2, DRD5, and APOA4 are among the most upregulated genes. MicroRNA analysis showed 12 miRNA differentially expressed between RCC and LCC. Conclusions: RCC and LCC have distinct molecular profiles, whereas LCC and RC appear to be similar at the genomic level. Several specific/novel gene mutations are associated particularly with RCC (APC and AMER1 genes among others). A novel driver gene, BAGE2, was discovered in a subset of colorectal cancers.