American Association for Cancer Research
10780432ccr173713-sup-193923_2_supp_4842513_prrcqz.doc (11.81 MB)

Figures S1-S7 from Mutational Analysis Identifies Therapeutic Biomarkers in Inflammatory Bowel Disease–Associated Colorectal Cancers

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journal contribution
posted on 2023-03-31, 21:47 authored by Shahida Din, Kim Wong, Mike F. Mueller, Anca Oniscu, James Hewinson, Catherine J. Black, Martin L. Miller, Alejandro Jiménez-Sánchez, Roy Rabbie, Mamunar Rashid, Jack Satsangi, David J. Adams, Mark J. Arends

Supplementary Figure S1: Exome sequencing fold coverage of inflammatory bowel disease associated colorectal cancer cases and matched normal lymph nodes. Supplementary Figure S2 Mismatch repair protein expression analysis. Supplementary Figure S3: CpG island methylation of MLH1 promoter region. Supplementary Figure S4: Rainfall plot for case 21M. Supplementary Figure S5: Proportion of IBC-CRC genomes with SCNAs. Supplementary Figure S6: Nanostring nCounter® pan-cancer immune panel analysis. Supplementary Figure S7: Validation of InDel mutations.


European Research Council

Cancer Research UK

Wellcome Trust

NHS Research Scotland (NRS)

Mexican National Council of Science and Technology (CONACyT)



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.