B Vitamins, Methionine and Alcohol Intake and Risk of Colon Cancer in Relation to BRAF Mutation and CpG Island Methylator Phenotype (CIMP)

One-carbon metabolism appears to play an important role in DNA methylation reaction. Evidence suggests that a low intake of B vitamins or high alcohol consumption increases colorectal cancer risk. How one-carbon nutrients affect the CpG island methylator phenotype (CIMP) or BRAF mutation status in colon cancer remains uncertain.Utilizing incident colon cancers in a large prospective cohort of women (the Nurses' Health Study), we determined BRAF status (N = 386) and CIMP status (N = 375) by 8 CIMP-specific markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT-1, MINT-31, p14, and WRN). We examined the relationship between intake of one-carbon nutrients and alcohol and colon cancer risk, by BRAF mutation or CIMP status.Higher folate intake was associated with a trend towards low risk of CIMP-low/0 tumors [total folate intake ≥400 µg/day vs. <200 µg/day; the multivariate relative risk = 0.73; 95% CI = 0.53-1.02], whereas total folate intake had no influence on CIMP-high tumor risks (P(heterogeneity) = 0.73). Neither vitamin B(6), methionine or alcohol intake appeared to differentially influence risks for CIMP-high and CIMP-low/0 tumors. Using the 16-marker CIMP panel did not substantially alter our results. B vitamins, methionine or alcohol intake did not affect colon cancer risk differentially by BRAF status.This molecular pathological epidemiology study suggests that low level intake of folate may be associated with an increased risk of CIMP-low/0 colon tumors, but not that of CIMP-high tumors. However, the difference between CIMP-high and CIMP-low/0 cancer risks was not statistically significant, and additional studies are necessary to confirm these observations

Pharmacoepidemiological approaches for population-based hypothesis testing

Pharmacoepidemiology aims to study the use and both the adverse and beneficial effects of drugs and vaccines in the population after market authorization. The efficacy of drugs is assessed in experimental studies before a drug is allowed on the market in a limited and usually selected group of patients. Therefore, after market authorization the focus is on serious and adverse effects in large groups of patients in daily clinical practice. Observational drug research is needed to establish and measure these effects. Observational research faces several challenges to minimize the chance of bias, including confounding by indication, which is caused by selective prescribing of drugs to certain patient groups. A comparison between treated and untreated subjects or between different drug regimens may be biased due to uneven distribution of risk factors for the outcome of interest. Important progress has been made during the past decade in controlling confounding by design and analysis in observational studies. The increasing accessibility of large electronic health record databases has fuelled various international initiatives to analyze multiple databases across countries using common protocols and common data models. Extensive sensitivity analysis across multiple designs, databases, and analytical techniques has provided more insight into causes of variation in results across studies and increases the confidence in findings of observational studies. Transparency of observational drug research through public registration of protocols and detailed reporting of methods should improve reproducibility and thereby reliability of pharmacoepidemiological studies