Authors:
S Din, K Wong, MF Müller, A Oniscu, J Hewinson, CJ Black, ML Miller, A Jiménez-Sánchez, R Rabbie, M Rashid, J Satsangi, DJ Adams, MJ Arends
Journal name: 
Clin Cancer Res
Abstract: 
PURPOSE: Inflammatory bowel disease-associated colorectal cancers (IBD-CRCs) 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 individualised 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 1 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 6 distinct mutation signatures in IBD-CRCs, 3 of which corresponded with 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 immunohistochemistry 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 individualise surveillance and treatment programmes.
DOI: 
http://doi.org/10.1158/1078-0432.CCR-17-3713
Research group: 
Miller Group
E-pub date: 
27 Jun 2018