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O-6-methylguanine-DNA methyltransferase (MGMT) repairs inappropriately methylated guanine residues in DNA.MGMTpromoter methylation and gene silencing are common events in colorectal cancer, and may or may not co-exist with the CpG island methylator phenotype (CIMP). To date, no study has examined the relationship betweenMGMTpromoter methylation and commonMGMTsingle nucleotide polymorphisms (SNPs), which have been associated with colorectal cancer risk. Utilizing real-time polymerase chain reaction (MethyLight technology), we quantified DNA methylation inMGMTand eight other markers (a CIMP diagnostic panel including CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1 in 182 colorectal cancers collected from two prospective cohorts, the Nurses’ Health Study and the Health Professionals Follow-up Study. We genotyped fourMGMTgermline SNPs in normal DNA and assessed microsatellite instability (MSI), 18q loss of heterozygosity andKRASandBRAFstatus in tumors. The presence of a commonMGMTpromoter SNP (NM_002412.2:c.-56C&gt;T) (rs16906252) was strongly associated withMGMTmethylation (multivariate odds ratio 18.0; 95% confidence interval, 6.2–52.1,P &lt; 0.0001). The presence of the c.-56C&gt;T SNP was also associated with loss of MGMT expression in tumors (assessed by immunohistochemistry) (P = 0.009). This promoter SNP was not correlated withKRAS,BRAF, CIMP or MSI status. None of the other three non-promoter SNPs was significantly associated with any molecular changes tested. In conclusion, we have found a strong association between the germline polymorphism (c.-56C&gt;T) of theMGMTpromoter and promoter methylation/silencing ofMGMTin colorectal cancer. Our data provide compelling evidence for common susceptibility forMGMTpromoter CpG island methylation.

carcinogenesis

MGMT               germline polymorphism is associated with somatic               MGMT               promoter methylation and gene silencing in colorectal cancer