Purpose:
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.Experimental Design: 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.Results: 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 POLE 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.Conclusions: 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. Clin
Cancer Res; 24(20); 5133-42. ©2018 AACR.