Somatic mutation profiles as molecular classifiers of ulcerative colitis‐associated colorectal cancer

Abstract

Ulcerative colitis increases colorectal cancer risk by mechanisms that remain incompletely understood. We approached this question by determining the genetic and epigenetic profiles of colitis-associated colorectal carcinomas (CA-CRC). The findings were compared to Lynch syndrome (LS), a different form of cancer predisposition that shares the importance of immunological factors in tumorigenesis. CA-CRCs (n = 27) were investigated for microsatellite instability, CpG island methylator phenotype and somatic mutations of 999 cancer-relevant genes ("Pan-cancer" panel). A subpanel of "Pan-cancer" design (578 genes) was used for LS colorectal tumors (n = 28). Mutational loads and signatures stratified CA-CRCs into three subgroups: hypermutated microsatellite-unstable (Group 1, n = 1), hypermutated microsatellite-stable (Group 2, n = 9) and nonhypermutated microsatellite-stable (Group 3, n = 17). The Group 1 tumor was the only one with MLH1 promoter hypermethylation and exhibited the mismatch repair deficiency-associated Signatures 21 and 15. Signatures 30 and 32 characterized Group 2, whereas no prominent single signature existed in Group 3. TP53, the most common mutational target in CA-CRC (16/27, 59%), was similarly affected in Groups 2 and 3, but DNA repair genes and Wnt signaling genes were mutated significantly more often in Group 2. In LS tumors, the degree of hypermutability exceeded that of the hypermutated CA-CRC Groups 1 and 2, and somatic mutational profiles and signatures were different. In conclusion, Groups 1 (4%) and 3 (63%) comply with published studies, whereas Group 2 (33%) is novel. The existence of molecularly distinct subgroups within CA-CRC may guide clinical management, such as therapy options.

Genetic and Epigenetic Characteristics of Inflammatory Bowel Disease–Associated Colorectal Cancer

“…4 We could not identify a distinct subgroup of MSS IBD-CRCs with elevated genome-wide mutation densities, as suggested earlier by panel sequencing. 62 Two negative feedback regulators induced by WNT signaling, AXIN2 and RNF43, were strongly down-regulated in IBD-CRCs compared to sCRCs. AXIN2 participates with APC in the b-catenin destruction complex, 63 while RNF43 inhibits upstream WNT signaling by inducing the degradation of frizzled receptors.…”

“…IBD-CRCs tended to show higher genome-wide methylation compared to sCRCs, but decreased exposure to mutational signature linked with age-driven deamination of 5'methylcytosines; the latter was found also when compared with tumors from patients with Lynch syndrome. 62 Neither were explained by the younger age at diagnosis or by differential expression of DNMT or TET enzymes regulating DNA methylation, suggesting inflammation-driven methylation changes.…”

Immunoprofiles and DNA Methylation of Inflammatory Marker Genes in Ulcerative Colitis-Associated Colorectal Tumorigenesis

“…Sampling was done before any cytostatic cancer treatments, either at the time of the diagnosis or the surgery. All LS adenomas had high-grade dysplasia and their molecular profiles (including MSI, CIMP, and somatic mutational status) were comparable to LS-CRCs, as detailed previously [21]. Therefore, LS adenomas and carcinomas were combined, and the respective results in this study are given for this joint group referred to as "LS tumors".…”

“…MSI status was investigated using mononucleotide repeat markers BAT25 and BAT26, as described in Mäki-Nevala et al [21]. The diagnosis of MSI required at least one unstable marker.…”

“…Commercial SALSA MS-MLPA ME042-B2 (for LS samples) and ME042-C1 (for CA-CRC samples) probe mixes (MRC Holland, Amsterdam, The Netherlands) were used according to the manufacturer's protocol. The results were interpreted as described in Mäki-Nevala et al [21] for CA-CRC and Valo et al [24] for LS. Briefly, eight established marker genes for CIMP (CACNA1G, CDKN2A, CRABP1, IGF2, NEUROG1, MLH1, RUNX3, and SOCS1) were investigated.…”