Abstract
The relationship between gene-specific DNA methylation in peripheral blood leukocytes and colorectal cancer (CRC) susceptibility is unclear. In this case-control study, the methylation status of a panel of 10 CRC-related genes in 428 CRC cases and 428 cancer-free controls were detected with methylation-sensitive high-resolution melting analysis. We calculated a weighted methylation risk score (MRS) that comprehensively combined the methylation status of the panel of 10 genes and found that the MRS_10 was significantly associated with CRC risk. Compared with MRS-Low group, MRS-High group and MRS-Medium group exhibited a 6.51-fold (95% CI, 3.77-11.27) and 3.85-fold (95% CI, 2.72-5.45) increased risk of CRC, respectively. Moreover, the CRC risk increased with increasing MRS_10 (Ptrend < 0.0001). Stratified analyses demonstrated that the significant association retained in both men and women, younger and older, and normal weight or underweight and overweight or obese subjects. The area under the receiver operating characteristic curves for the MRS_10 model was 69.04% (95% CI, 65.57-72.66%) and the combined EF and MRS_10 model yielded an AUC of 79.12% (95% CI, 76.22-82.15%). Together, the panel of 10 gene-specific DNA methylation in leukocytes was strongly associated with the risk of CRC and might be a useful marker of susceptibility for CRC.
Highlights
Colorectal cancer (CRC), with an estimated 1,360,602 newly diagnosed cases and 693,933 deaths in 2012, is the third-most common cancer in men and the second-most in women worldwide [1]
Some studies focused on genomic methylation of leukocyte DNA in relation to the risk colorectal cancer (CRC) [16,17,18,19] or colorectal adenomas [20, 21], and other studies have reported an association between gene-specific methylation in leukocytes and the risk of CRC [22,23,24,25,26] or colorectal adenomas [27,28,29]
For DAPK1 and MLH1, the methylation status obtained via Methylation-sensitive high-resolution melting (MS-HRM) was compared with the mean methylation level based on quantitative pyrosequencing and the results indicated that the MS-HRM results were well confirmed by the pyrosequencing results (Supplementary Figure 1)
Summary
Colorectal cancer (CRC), with an estimated 1,360,602 newly diagnosed cases and 693,933 deaths in 2012, is the third-most common cancer in men and the second-most in women worldwide [1]. Several studies have reported gene-specific methylation alterations in leukocytes from patients with various cancers, including bladder, breast, renal, and head and neck cancer [30,31,32,33,34]. The results of these studies did imply aberrant methylation of multiple genes in leukocytes might predispose toward susceptibility to CRC, like genetic variants of germline DNA. We carried out this case-control study to investigate the associations between leukocyte-derived DNA methylation in a panel of 10 genes and the risk of CRC
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