Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease−Associated Colorectal Cancers

Abstract

BACKGROUND & AIMS A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer (CRC). Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors. METHODS We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and CRC (15 with ulcerative colitis, 14 with Crohn’s disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the micro-dissected tumor and matched non-tumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies. RESULTS Two specimens had somatic mutations in the DNA-proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with and incidence prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for non-canonical WNT signaling in development of colorectal tumors in patients with IBD. CONCLUSIONS Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and CRC.

Colitic Cancer Develops Through Mutational Alteration Distinct from that in Sporadic Colorectal Cancer: A Comparative Analysis of Mutational Rates at Each Step

“…In this study, we found a much lower mutational rate of KRAS than that of sporadic cancer, compatible to a previous report (19). KRAS plays a key role in intracellular signal transduction pathways, and its mutation is observed in approximately 40% of CRC.…”

Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers

“…This difference might be due to the few adenomas exhibiting a high number of mutations, perhaps they are beginning to exhibit a hypermutable phenotype. While testing for MSI was not performed on the adenomas, the adenoma from sample ID 3 which contained 585 non‐synonymous mutations contained both a POLE (L1561fs) and a POLD3 mutation (Q104fs) consistent with a hypermutable phenotype 32. No known cause for hypermutability was identified in the adenoma from sample ID 6 which contained 434 non‐synonymous mutations.…”

Hypoxia-inducible factors: a central link between inflammation and cancer

“…This process includes the acquisition of sequential mutations leading to the loss of adenomatous-polyposis coli (APC) tumor suppressor, activation of the oncogene KRAS, and loss of the TP53 tumor suppressor (27). Interestingly, in colon cancers preceded by chronic inflammation due to IBD, the kinetics of the genetic alterations are different, as TP53 is lost early in disease progression and APC mutations are not as frequently observed compared to sporadic colon cancer (28,29). These data suggest that inflammation may induce novel mechanisms to drive cellular proliferation and survival, resulting in tumorigenesis.…”