Abstract
Simple SummaryIn colorectal cancer (CRC), mutations may occur in short, repeated DNA sequences, known as microsatellite instability (MSI). Tumor DNA methylation is another molecular change now recognized as an important biomarker in CRC. In a genome-wide scale, for the first time, we explored whether DNA methylation is associated with MSI status in CRC. We analyzed 250 paired samples (tumor and corresponding normal) from 125 CRC patients (m = 72, f = 53) at different stages. We found that many genes were methylated in tumor tissue compared to normal tissue. However, almost four times more genes showed such methylation changes in the tumor if the patient who also had MSI compared to patients without MSI. Our study shows an association of MSI and DNA methylation in CRC. The study also indicates an opportunity for potential use of certain immune checkpoint inhibitors (CTLA4 and HAVCR2 inhibitors) in CRC with MSI.In colorectal cancer (CRC), the role of microsatellite instability (MSI) is well known. In a genome-wide scale, for the first time, we explored whether differential methylation is associated with MSI. We analyzed 250 paired samples from 125 CRC patients (m = 72, f = 53) at different stages. Of them, 101 had left-sided CRC, 30 had MSI, 34 had somatic mutation in KRAS proto-oncogene (KRAS), and 6 had B-Raf proto-oncogene (BRAF) exon 15p.V600E mutation. MSI was more frequent in right-sided tumors (54% vs. 17%, p = 0.003). Among the microsatellite stable (MSS) CRC, a paired comparison revealed 1641 differentially methylated loci (DML) covering 686 genes at FDR 0.001 with delta beta ≥ 20%. Similar analysis in MSI revealed 6209 DML covering 2316 genes. ANOVA model including interaction (Tumor*MSI) revealed 23,322 loci, where the delta beta was different among MSI and MSS patients. Our study shows an association between MSI and tumor DNA methylation in the pathogenesis of CRC. Given the interaction seen in this study, it may be worth considering the MSI status while looking for methylation markers in CRC. The study also indicates an opportunity for potential use of certain immune checkpoint inhibitors (CTLA4 and HAVCR2 inhibitors) in CRC with MSI.
Highlights
Chromosomal instability and microsatellite instability (MSI) are distinct, well-described pathways of colorectal carcinoma (CRC) [1,2]
We explored if the difference in methylation between the tumor and healthy tissue for any loci within the mismatch repair (MMR) genes was significantly different in the MSI tumors compared to the microsatellite stable (MSS) tumors
When we looked at these 107 loci (Figure 6), a few, but not all of the loci in SOCS1, RUNX3, CRABP1, and NEUROG1 showed a statistically significant interaction of MSI and the tumor, suggesting greater differential methylation in MSI tumors
Summary
Chromosomal instability and microsatellite instability (MSI) are distinct, well-described pathways of colorectal carcinoma (CRC) [1,2]. One study showed hypermethylation of the p16 gene was found in 60% of MSI tumors compared to. The same study showed the association of hypermethylation of thrombospondin-1 (TSP-1), insulin like growth factor 1 (IGF2), and hypermethylated in cancer 1 (HIC-1) with MSI tumors [8]. In all these studies, the associations were tested in a handful of targeted genes. In the present genome-wide methylation study in humans, we explored whether the differential methylation of tumor DNA in CRC is associated with the MSI status of the tumor
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