The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status.

PURPOSE: The aim of this study was to relate the CpG island methylator phenotype (CIMP; characterized by extensive promoter hypermethylation) to cancer-specific survival in colorectal cancer, taking into consideration relevant clinicopathologic factors, such as microsatellite instability (MSI) screening status and the BRAF V600E mutation. EXPERIMENTAL DESIGN: Archival tumor samples from 190 patients from the Northern Sweden Health and Disease Study (NSHDS) and 414 patients from the Colorectal Cancer in Umeå Study (CRUMS), including 574 with cancer-specific survival data, were analyzed for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). MSI screening status was assessed by immunohistochemistry. RESULTS: CIMP-low patients had a shorter cancer-specific survival compared with CIMP-negative patients (multivariate hazard ratio in NSHDS, 2.01; 95% confidence interval, 1.20-3.37; multivariate hazard ratio in CRUMS, 1.48; 95% confidence interval, 1.00-2.22). This result was similar in subgroups based on MSI screening status and was statistically significant in microsatellite stable (MSS) tumors in NSHDS. For CIMP-high patients, a shorter cancer-specific survival compared with CIMP-negative patients was observed in the MSS subgroup. Statistical significance was lost after adjusting for the BRAF mutation, but the main findings were generally unaffected. CONCLUSIONS: In this study, we found a poor prognosis in CIMP-low patients regardless of MSI screening status, and in CIMP-high patients with MSS. Although not consistently statistically significant, these results were consistent in two separate patient groups and emphasize the potential importance of CIMP and MSI status in colorectal cancer research.

Polymorphisms of methylenetetrahydrofolate reductase and the risk of prostate cancer: a nested case-control study.

It has been proposed that folate and polymorphisms of the enzyme methylenetetrahydrofolate reductase (MTHFR), which regulates influx of folate from DNA synthesis and repair to methylation reactions, are involved in the aetiology of cancer. To relate the MTHFR 677C-->T and 1298A-->C polymorphisms to the risk of prostate cancer, taking into consideration prospective plasma levels of folate, vitamin B12 and homocysteine. The design was a case-control study of 223 prostate cancer cases and 435 matched controls nested within the population-based Northern Sweden Health and Disease Cohort. Neither the MTHFR 677C-->T nor the MTHFR 1298A-->C polymorphism was statistically significantly associated with the risk of prostate cancer in univariate analysis by conditional logistic regression. After adjustment for MTHFR 1298A-->C, plasma folate, vitamin B12, homocysteine, body mass index and smoking, the odds ratios were, for the 677 CT genotype, 1.52 [95% confidence interval (CI) 1.02-2.26], and for TT, 0.91 (95% CI 0.41-2.04). Our previously reported observation of a possible increase in the risk of prostate cancer at high plasma folate levels was attributable in this study to subjects having the MTHFR 677C-->T polymorphism. We found that the MTHFR 677C-->T polymorphism is not likely to have a major role in the development of prostate cancer, although it may possibly increase the risk in combination with high plasma folate levels. Further investigation in larger studies is warranted.