BackgroundThe methylenetetrahydrofolate reductase gene (MTHFR) is one of the most investigated genes associated with breast cancer for its role in epigenetic pathways.ObjectivesThe objectives of this metaprediction study were to examine the polymorphism-mutation risk subtypes of MTHFR and air pollution as contributing factors for breast cancer.MethodsFor triangulation purposes in metapredictive analyses, we used a recursive partition tree, nonlinear association curve fit, and heat maps for data visualization, in addition to the conventional comparison procedure and pooled analyses.ResultsWe included 36,683 breast cancer cases and 40,689 controls across 82 studies for MTHFR 677 and 23,252 cases and 27,094 controls across 50 studies for MTHFR 1298. MTHFR 677 TT was a risk genotype for breast cancer (p = .0004) and in the East Asian subgroup (p = .005). On global maps, the most polymorphism-mutations on MTHFR 677 TT were found in the Middle East, Europe, Asia, and the Americas, whereas the most mutations on MTHFR 1298 CC were located in Europe and the Middle East for the control group. The geographic information system maps further revealed that MTHFR 677 TT mutations yielded a higher risk of breast cancer for Australia, East Asia, the Middle East, South Europe, Morocco, and the Americas and that MTHFR 1298 CC mutations yielded a higher risk in Asia, the Middle East, South Europe, and South America. Metapredictive analysis revealed that air pollution level was significantly associated with MTHFR 677 TT polymorphism-mutation genotype.DiscussionWe present the most comprehensive analyses to date of MTHFR polymorphism-mutations and breast cancer risk. Future nursing studies are needed to investigate the health impact on breast cancer of epigenetics and air pollution across populations.

Breast cancer (BC) is the most common cancer in women worldwide and second leading cause of cancer-related death. Understanding gene-environment interactions could play a critical role for next stage of BC prevention efforts. Hence, the purpose of this study was to examine the key gene-environmental factors affecting the risks of BC in a diverse sample. Five genes in one-carbon metabolism pathway including MTHFR 677, MTHFR 1298, MTR 2756, MTRR 66, and DHFR 19bp together with demographics, lifestyle, and dietary intake factors were examined in association with BC risks. A total of 80 participants (40 BC cases and 40 family/friend controls) in southern California were interviewed and provided salivary samples for genotyping. We presented the first study utilizing both conventional and new analytics including ensemble method and predictive modeling based on smallest errors to predict BC risks. Predictive modeling of Generalized Regression Elastic Net Leave-One-Out demonstrated alcohol use (p = 0.0126) and age (p < 0.0001) as significant predictors; and significant interactions were noted between body mass index (BMI) and alcohol use (p = 0.0027), and between BMI and MTR 2756 polymorphisms (p = 0.0090). Our findings identified the modifiable lifestyle factors in gene-environment interactions that are valuable for BC prevention.