A study analyzed over 70 pairs of primary human colon tumors using next-generation sequencing to characterize exomes, transcriptomes, and copy-number alterations. They identified 36,303 protein-altering somatic changes, including new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodeling genes like TET2 and TET3, and receptor tyrosine kinases such as ERBB3. The analysis identified 23 significantly mutated cancer genes, including ATM, and found amplifications and overexpression of IGF2 in some tumors. Recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 were identified in 10% of colon tumors. These fusions were mutually exclusive with APC mutations and likely activate Wnt signaling, promoting tumorigenesis. The R-spondin fusions and other mutations identified provide new therapeutic opportunities for colon cancer. Colorectal cancer (CRC) is the fourth most common cancer, with over 50,000 deaths annually in the US. Approximately 15% of CRCs have microsatellite instability (MSI) due to DNA mismatch repair (MMR) defects, while the remaining 85% are microsatellite-stable (MSS) due to chromosomal instability. Genomic studies have identified mutations, structural variants, and pathway alterations contributing to CRC development. The study sequenced exomes, RNA-seq, SNP arrays, and whole-genomes of 74 colon tumor-normal pairs. Exome sequencing identified 95,075 somatic mutations, with 36,303 being protein-altering. MSI samples had higher mutation rates, and mutations were consistent with MMR defects. Analysis of mutations showed C to T transitions were predominant in CRCs, regardless of MMR status. SIFT, PolyPhen, and mCluster identified 34% of mutations as likely functional. The study identified 23 significantly mutated cancer genes, including known genes like KRAS, APC, and TP53, and new genes like ATM. The study identified 356 of 432 candidate CRC genes from mouse model screens. Frequently mutated genes included KRAS, APC, SMAD4, FBXW7, and EP400. TCF12, a CRC gene, was mutated in five of 15 MSI samples. Mutations in TCF12's helix-loop-helix domain likely abolish its DNA-binding ability. RNA-seq identified differentially expressed genes, including FOXQ1 and CLDN1, and IGF2 upregulation in 12% of samples. Copy-number alterations included IGF2 amplifications, KRAS, and MYC amplifications, and deletions of FHIT, APC, PTEN, and SMAD3. The study identified 36 gene fusions,A study analyzed over 70 pairs of primary human colon tumors using next-generation sequencing to characterize exomes, transcriptomes, and copy-number alterations. They identified 36,303 protein-altering somatic changes, including new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodeling genes like TET2 and TET3, and receptor tyrosine kinases such as ERBB3. The analysis identified 23 significantly mutated cancer genes, including ATM, and found amplifications and overexpression of IGF2 in some tumors. Recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 were identified in 10% of colon tumors. These fusions were mutually exclusive with APC mutations and likely activate Wnt signaling, promoting tumorigenesis. The R-spondin fusions and other mutations identified provide new therapeutic opportunities for colon cancer. Colorectal cancer (CRC) is the fourth most common cancer, with over 50,000 deaths annually in the US. Approximately 15% of CRCs have microsatellite instability (MSI) due to DNA mismatch repair (MMR) defects, while the remaining 85% are microsatellite-stable (MSS) due to chromosomal instability. Genomic studies have identified mutations, structural variants, and pathway alterations contributing to CRC development. The study sequenced exomes, RNA-seq, SNP arrays, and whole-genomes of 74 colon tumor-normal pairs. Exome sequencing identified 95,075 somatic mutations, with 36,303 being protein-altering. MSI samples had higher mutation rates, and mutations were consistent with MMR defects. Analysis of mutations showed C to T transitions were predominant in CRCs, regardless of MMR status. SIFT, PolyPhen, and mCluster identified 34% of mutations as likely functional. The study identified 23 significantly mutated cancer genes, including known genes like KRAS, APC, and TP53, and new genes like ATM. The study identified 356 of 432 candidate CRC genes from mouse model screens. Frequently mutated genes included KRAS, APC, SMAD4, FBXW7, and EP400. TCF12, a CRC gene, was mutated in five of 15 MSI samples. Mutations in TCF12's helix-loop-helix domain likely abolish its DNA-binding ability. RNA-seq identified differentially expressed genes, including FOXQ1 and CLDN1, and IGF2 upregulation in 12% of samples. Copy-number alterations included IGF2 amplifications, KRAS, and MYC amplifications, and deletions of FHIT, APC, PTEN, and SMAD3. The study identified 36 gene fusions,