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Clin Cancer Res. 2018 Oct 15;24(20):5133-5142. doi: 10.1158/1078-0432.CCR-17-3713. Epub 2018 Jun 27.

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

Author information

1
NHS Lothian, Gastrointestinal Unit, Western General Hospital, Edinburgh, Scotland, United Kingdom. sdin@ed.ac.uk.
2
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
3
Division of Pathology, Centre for Comparative Pathology, Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
4
NHS Lothian, Department of Molecular Pathology, Laboratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kingdom.
5
NHS Lothian, Department of Pathology, Western General Hospital, Edinburgh, Scotland, United Kingdom.
6
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, United Kingdom.
7
Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
#
Contributed equally

Abstract

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.

PMID:
29950348
PMCID:
PMC6193541
DOI:
10.1158/1078-0432.CCR-17-3713
[Indexed for MEDLINE]
Free PMC Article

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