Whole Exome Sequencing of Ulcerative Colitis-associated Colorectal Cancer Based on Novel Somatic Mutations Identified in Chinese Patients.

ABSTRACT

BACKGROUND: Carcinogenesis is a severe consequence of chronic ulcerative colitis. We investigated the somatic mutations and pathway alterations in ulcerative colitis-associated colorectal cancer (CRC) in Chinese patients compared with sporadic CRCs to reveal potential therapeutic targets in ulcerative colitis-associated CRC. METHODS: Whole exome sequencing was performed on archival tumor tissues and paired adjacent nondysplastic mucosa from 10 ulcerative colitis-associated CRC patients at a high risk of carcinogenesis. Genomic alteration profiles from 223 primary CRCs from The Cancer Genome Atlas served as sporadic CRC controls. A meta-analysis was performed to investigate differences in major genetic mutations between ulcerative colitis-associated and Crohn's disease-associated CRCs. RESULTS: We identified 44 nonsilent recurrent somatic mutations via whole exome sequencing, including 25 deleterious mutations involved in apoptosis and the PI3K-Akt pathway (COL6A3, FN1), autophagy (ULK1), cell adhesion (PODXL, PTPRT, ZFHX4), and epigenetic regulation (ARID1A, NCOR2, KMT2D, NCOA6, MECP2, SUPT6H). In total, 11 of the 25 mutated genes significantly differed between ulcerative colitis-associated CRC and sporadic CRC (APC, APOB, MECP2, NCOR2, NTRK2, PODXL, RABGAP1, SIK3, SUPT6H, ULK1, USP48). Somatic TP53 mutations occurred in 33% of ulcerative colitis-associated CRCs. Subsequent meta-analysis revealed distinct mutation profiles for Crohn's disease- and ulcerative colitis-associated CRCs. Mutations involving the NF-kB pathway and epigenetic regulation were more common in ulcerative colitis-associated CRCs than in sporadic CRCs. CONCLUSION: Distinct genomic alteration profiles of deleterious somatic mutations were found in ulcerative colitis-associated and sporadic CRCs. Mutations of epigenetic regulators, such as KMT2D and NCOA6, were common, suggesting an epigenetic pathomechanism for colitis-associated carcinoma in Chinese patients.