Abstract
Chronic inflammation increases cancer risk, and cancer development is characterized by stepwise accumulation of genetic and epigenetic alterations. During chronic inflammation, infectious agents and intrinsic mediators of inflammatory responses can induce genetic and epigenetic changes. This study tried to evaluate both the genetic and epigenetic influence of chronic inflammation on colon mucosa cells. Repetitive dextran sulfate sodium (DSS) treatment induced chronic colitis model. Whole-exome sequencing (WES) (200× coverage) was performed to detect somatic variations in colon mucosa cells. With the use of whole-genome bisulfite sequencing (BS) at 34-fold coverage (17-fold per strand), the methylome of both the colitis and control tissue was comparatively analyzed. Bioinformatics assay showed that there was no significant single-nucleotide polymorphism/insertion or deletion (SNP/InDel) mutation accumulation in colitis tissue, while it accumulated in aged mice. Forty-eight genes with SNP/InDel mutation were overlapped in the three colitis tissues, two (Wnt3a and Lama2) of which are in the cancer development-related signaling pathway. Differentially methylated region (DMR) assay showed that many genes in the colitis tissue are enriched in the cancer development-related signaling pathway, such as PI3K–AKT, Ras, Wnt, TGF-beta, and MAPK signaling pathway. Together, these data suggested that even though chronic inflammation did not obviously increase genetic mutation accumulation, it could both genetically and epigenetically alter some genes related to cancer development.
Highlights
Chronic inflammation has been indicated as an important risk factor for cancer; one of the best examples of the association between chronic inflammation and cancer is found in the heightened predisposition for cancer of patients suffering from ulcerative colitis (UC) and Crohn’s disease of the colon, the major forms of idiopathic inflammatory bowel disease (McLarnon, 2011; Risques et al, 2011)
We found that the single-nucleotide polymorphisms (SNPs)/insertion or deletion (InDel) number was obviously elevated in the older mice compared with the young mice, suggesting that aging could make significant contribution to accumulation of somatic mutation
Even though somatic SNP/InDel/copy number variation (CNV) number was not increased by chronic inflammation, we found that the SNP/ InDel number was obviously elevated in the older mouse (56W, SNP/InDel: 860) compared with the young mouse (8 weeks old, SNP/InDel: 629) (Figure 2F)
Summary
Chronic inflammation has been indicated as an important risk factor for cancer; one of the best examples of the association between chronic inflammation and cancer is found in the heightened predisposition for cancer of patients suffering from ulcerative colitis (UC) and Crohn’s disease of the colon, the major forms of idiopathic inflammatory bowel disease (McLarnon, 2011; Risques et al, 2011). Extensive and chronic UC leads to a 19-fold increase in risk for colon cancer, and about 5% of UC patients develop tumors (Gillen et al, 1994). We present the characteristic of the somatic variation of exome in colon mucosa cells of three chronic colitis mice via WES approaches, the colitis was induced via dextran sulfate sodium (DSS) repeatedly for 40 weeks, and age-matched and no-DSS-treated mice serve as the control mice. Functional analysis showed that differentially methylated genes in chronic inflammation are enriched in the signal pathways related to carcinogenesis. These all suggest that a part of genes related to cancer development appears to have both genetic and epigenetic alterations by chronic inflammation
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