A comprehensive molecular characterization of human colon and rectal cancer was conducted using genome-scale analysis of 276 samples, including exome sequencing, DNA copy number, promoter methylation, and mRNA and microRNA expression. The study identified 16% of colorectal carcinomas as hypermutated, with most having high microsatellite instability and MLH1 silencing, and a quarter having somatic mismatch-repair gene and POLE mutations. Non-hypermutated cancers showed similar genomic patterns. Twenty-four genes were significantly mutated, including APC, TP53, SMAD4, PIK3CA, and KRAS, with additional frequent mutations in ARID1A, SOX9, and FAM123B. Recurrent copy-number alterations included ERBB2 amplification and IGF2 amplification, while chromosomal translocations included NAV2-TCF7L1 fusion. Integrative analyses identified new markers for aggressive colorectal cancer and highlighted the role of MYC in transcriptional activation and repression. The study also identified 257 tumors with SCNAs, including 97 analyzed by low-depth-of-coverage whole-genome sequencing. Chromosomal and sub-chromosomal changes were analyzed, revealing 28 recurrent deletion peaks and 17 focal amplifications. The 11p15.5 region was found to have significant amplification, with IGF2 and miR-483 as potential functional targets. Translocations were identified, including NAV2-TCF7L1 and TTC28 fusions. Altered pathways in CRC included WNT, MAPK, PI3K, TGF-β, and p53, with significant mutations in genes such as CTNNB1, SOX9, and FAM123B. The study also identified molecular signatures associated with tumor aggressiveness, including specific focal amplifications, deletions, and altered gene-expression levels. The findings suggest that hypermutated and non-hypermutated tumors progress through different genetic events. The study provides insights into the molecular mechanisms of CRC and identifies potential therapeutic targets, including WNT signaling inhibitors and small-molecule β-catenin inhibitors. The data also highlight the importance of MYC in CRC and the role of IGF2 and miR-483 in tumor progression. The study underscores the need for further research into the genetic and genomic changes in colorectal cancer to improve diagnosis and treatment strategies.A comprehensive molecular characterization of human colon and rectal cancer was conducted using genome-scale analysis of 276 samples, including exome sequencing, DNA copy number, promoter methylation, and mRNA and microRNA expression. The study identified 16% of colorectal carcinomas as hypermutated, with most having high microsatellite instability and MLH1 silencing, and a quarter having somatic mismatch-repair gene and POLE mutations. Non-hypermutated cancers showed similar genomic patterns. Twenty-four genes were significantly mutated, including APC, TP53, SMAD4, PIK3CA, and KRAS, with additional frequent mutations in ARID1A, SOX9, and FAM123B. Recurrent copy-number alterations included ERBB2 amplification and IGF2 amplification, while chromosomal translocations included NAV2-TCF7L1 fusion. Integrative analyses identified new markers for aggressive colorectal cancer and highlighted the role of MYC in transcriptional activation and repression. The study also identified 257 tumors with SCNAs, including 97 analyzed by low-depth-of-coverage whole-genome sequencing. Chromosomal and sub-chromosomal changes were analyzed, revealing 28 recurrent deletion peaks and 17 focal amplifications. The 11p15.5 region was found to have significant amplification, with IGF2 and miR-483 as potential functional targets. Translocations were identified, including NAV2-TCF7L1 and TTC28 fusions. Altered pathways in CRC included WNT, MAPK, PI3K, TGF-β, and p53, with significant mutations in genes such as CTNNB1, SOX9, and FAM123B. The study also identified molecular signatures associated with tumor aggressiveness, including specific focal amplifications, deletions, and altered gene-expression levels. The findings suggest that hypermutated and non-hypermutated tumors progress through different genetic events. The study provides insights into the molecular mechanisms of CRC and identifies potential therapeutic targets, including WNT signaling inhibitors and small-molecule β-catenin inhibitors. The data also highlight the importance of MYC in CRC and the role of IGF2 and miR-483 in tumor progression. The study underscores the need for further research into the genetic and genomic changes in colorectal cancer to improve diagnosis and treatment strategies.