The in situ expression of 10 genes was assessed by the immunohistochemical approach at the protein level: CDH1, CDH13, COX2, cyclin A1, hMLH1, MGMT, p14(ARF), p73, RAR- , and TIMP3 genes in the context of the methylation status in colorectal cancer.
Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p16(INK4a), p14(ARF), MGMT, GSTP1 and RARbeta2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n = 215) breast and colorectal cancers.
Its combination with hypermethylated in cancer 1 (HIC1), death-associated protein kinase (DAPK) and O-6-methylguanine DNA methyltransferase (MGMT), allowed the detection of aberrant methylation in 98% of colorectal carcinomas and 100% of gastric carcinomas.
The aim of our study was to evaluate the activity of temozolomide in terms of response rate in patients with metastatic CRC and MGMT methylation, after failure of approved treatments.
Alkylating agents, such as dacarbazine, exert their antitumor activity by DNA methylation at the O(6)-guanine site, inducing base pair mismatch; therefore, activity of dacarbazine could be enhanced in CRCs lacking MGMT.
BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1, whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT.
Nineteen percent of the screened population (137/740) had confirmed tissue and/or serum MGMT promoter methylation, including 25% (57 of 229) for CRC, 36% (55 of 154) for esophageal cancer, 11% (12 of 113) for head and neck cancer, and 5% (13 of 242) for non-small cell lung carcinoma.
Despite a well-established role of MGMT aberrations in carcinogenesis, neither MGMT promoter methylation nor MGMT loss serves as a prognostic biomarker in colorectal cancer.
To identify which CpG sites are critical for its downregulation, we analyzed the methylation status of the MGMT gene promoter in two sites in CRC patients.
The frequency of MGMT promoter hypermethylation in UC-associated CRCs found in this study (16.7%) is obviously lower than previously reported in sporadic CRCs (39.0-42.0%).
Our results suggest that the common Leu84Phe and Ile143Val polymorphisms in MGMT influence risk of colorectal cancer in women possibly through modulating estrogen receptor-dependent transcriptional activation, which has previously been shown to occur in response to DNA alkylation damage.
These findings paralleled immunohistochemical patterns of hMLH1 and MGMT protein loss in an independent series of 231 colorectal cancers and were consistent with current epigenetic profiles of colorectal cancer subsets.
Methylated secreted frizzled-related protein gene 2 (SFRP2), hyperplastic polyposis protein gene (HPP1) and O6-methylguanine-DNA methyltransferase gene (MGMT) in stools from 52 patients with CRC, 35 patients with benign colorectal diseases and 24 normal individuals were analyzed using methylation-specific PCR.
Mean total MGMT level varied between tumor types: 554 +/- 404 fmol/mg protein (+/-SD) for prostate cancer, 87.4 +/- 40.3 fmol/mg protein for CNS tumors, and 244 +/- 181 fmol/mg protein for colorectal cancer.
The methylation frequencies of MGMT gene promoter were 41.4%, 34.2%, and 44.2% in stomach, esophageal, and colorectal cancer cases while as 16.6, 13.3, and 13.3 in respective controls.
Methylation of the CpG island in the MGMT promoter region is a frequent event in several cancer types including colorectal cancer, lung cancer, lymphoma, and glioblastoma.
In conclusion, this meta-analysis suggests that the PARP-1 rs1136410: T > C polymorphism is a susceptibility factor for GI cancers, but the variant allele of MGMTrs12917: C > T polymorphism appears to be a protective factor for colorectal cancer.