Mutational Analysis Identifies Therapeutic Biomarkers in Inflammatory Bowel Disease–Associated Colorectal Cancers

Abstract

Inflammatory bowel disease-associated colorectal cancers (IBD-CRC) are associated with a higher mortality than sporadic colorectal cancers. The poorly defined molecular pathogenesis of IBD-CRCs limits development of effective prevention, detection, and treatment strategies. We aimed to identify biomarkers using whole-exome sequencing of IBD-CRCs to guide individualized management. Whole-exome sequencing was performed on 34 formalin-fixed paraffin-embedded primary IBD-CRCs and 31 matched normal lymph nodes. Computational methods were used to identify somatic point mutations, small insertions and deletions, mutational signatures, and somatic copy number alterations. Mismatch repair status was examined. Hypermutation was observed in 27% of IBD-CRCs. All hypermutated cancers were from the proximal colon; all but one of the cancers with hypermutation had defective mismatch repair or somatic mutations in the proofreading domain of DNA Hypermutated IBD-CRCs had increased numbers of predicted neo-epitopes, which could be exploited using immunotherapy. We identified six distinct mutation signatures in IBD-CRCs, three of which corresponded to known mechanisms of mutagenesis. Driver genes were also identified. IBD-CRCs should be evaluated for hypermutation and defective mismatch repair to identify patients with a higher neo-epitope load who may benefit from immunotherapies. Prospective trials are required to determine whether IHC to detect loss of MLH1 expression in dysplastic colonic tissue could identify patients at increased risk of developing IBD-CRC. We identified mutations in genes in IBD-CRCs with hypermutation that might be targeted therapeutically. These approaches would complement and individualize surveillance and treatment programs. .

Molecular characterization of ulcerative colitis-associated colorectal carcinomas

“…Our genetic profiling of UC-CRC development confirmed TP53 mutations as a key event of chronic inflammation-driven colorectal carcinogenesis occurring in 87% (20 of 23) of UC-CRC samples. This is in concordance with previous next generation sequencing based publications reporting TP53 mutation frequencies in UC-CRC of 57% (n = 7) ( 15 ), 63% (n = 16) ( 16 ), 53% (n = 15) ( 17 ), and 86% (n = 29) ( 18 ), respectively. Comparable TP53 mutation frequencies have also been observed in CD-CRC with 100% (n = 3) ( 15 ), 88% (n = 8) ( 16 ), 76% (n = 29) ( 39 ), 69% (n = 13) ( 17 ) and 94% (n = 18) ( 18 ), respectively.…”

“…This is in concordance with previous next generation sequencing based publications reporting TP53 mutation frequencies in UC-CRC of 57% (n = 7) ( 15 ), 63% (n = 16) ( 16 ), 53% (n = 15) ( 17 ), and 86% (n = 29) ( 18 ), respectively. Comparable TP53 mutation frequencies have also been observed in CD-CRC with 100% (n = 3) ( 15 ), 88% (n = 8) ( 16 ), 76% (n = 29) ( 39 ), 69% (n = 13) ( 17 ) and 94% (n = 18) ( 18 ), respectively. Mutations in other genes were infrequent in both UC-CRC and CD-CRC.…”

Somatic Evolution in Non-neoplastic IBD-Affected Colon

“…SBS32, however, would only be expected in patients receiving purine therapy and so would not be present in sporadic colorectal cancers. These signatures have also not been reported in studies of colitis-associated colorectal cancers but this is likely due to a relative lack of power due to the small number of sequenced exomes ( Robles et al., 2016 ; Baker et al., 2019 ; Din et al., 2018 ).

Figure S3 Phylogenetic Trees for All Crohn’s Disease Patients, Related to Figures 2 , 4 , and 6 Mutational signatures are overlaid on the trees and putative driver mutations are mapped to the branch in which they occur.

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Ginger Alleviates DSS-Induced Ulcerative Colitis Severity by Improving the Diversity and Function of Gut Microbiota

“…Epidemiological research has also shown that antibiotics over-scavenge the gut flora, causing macrophages to overreact to bacteria, thereby disrupting oxidative phosphorylation. Hypermutation occurs in 27% of IBD-associated colorectal cancer cases, including DNA repair dysfunction ( Din et al, 2018 ). Lipopolysaccharide isolated from Helicobacter disrupts intestinal DNA repair, increasing the risk of permanent genotoxic effects, contributing to IBD or colon cancer ( Cavallo et al, 2011 ).…”