Pengguang Yan1,2, Yanan Wang2, Xiangchen Meng2, Hong Yang2, Zhanju Liu3, Jiaming Qian2, Weixun Zhou4, Jingnan Li2. 1. Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China. 2. Department of Gastroenterology, Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Chinese Academy of Medical Science, No. 1 Shuaifuyuan, Beijing, China. 3. Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China. 4. Department of pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, No. 1 Shuaifuyuan, Beijing, China.
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.
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.
Authors: Matthew H Bailey; William U Meyerson; Lewis Jonathan Dursi; Liang-Bo Wang; Guanlan Dong; Wen-Wei Liang; Amila Weerasinghe; Shantao Li; Yize Li; Sean Kelso; Gordon Saksena; Kyle Ellrott; Michael C Wendl; David A Wheeler; Gad Getz; Jared T Simpson; Mark B Gerstein; Li Ding Journal: Nat Commun Date: 2020-09-21 Impact factor: 14.919