Polymorphisms in DNA repair genes, recreational physical activity and breast cancer risk

The mechanisms driving the inverse association between recreational physical activity (RPA) and breast cancer risk are complex. While exercise is associated with increased reactive oxygen species production it may also improve damage repair systems, particularly those that operate on single-strand breaks including base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR). Of these repair pathways, the role of MMR in breast carcinogenesis is least investigated. Polymorphisms in MMR or other DNA repair gene variants may modify the association between RPA and breast cancer incidence. We investigated the individual and joint effects of variants in three MMR pathway genes (MSH3, MLH1 and MSH2) on breast cancer occurrence using resources from the Long Island Breast Cancer Study Project. We additionally characterized interactions between RPA and genetic polymorphisms in MMR, BER and NER pathways. We found statistically significant multiplicative interactions (p < 0.05) between MSH2 and MLH1, as well as between postmenopausal RPA and four variants in DNA repair (XPC-Ala499Val, XPF-Arg415Gln, XPG-Asp1104His and MLH1-lle219Val). Significant risk reductions were observed among highly active women with the common genotype for XPC (OR = 0.54; 95% CI, 0.36-0.81) and XPF (OR = 0.62; 95% CI, 0.44-0.87), as well as among active women who carried at least one variant allele in XPG (OR = 0.46; 95% CI, 0.29-0.77) and MLH1 (OR = 0.46; 95% CI, 0.30-0.71). Our data show that women with minor alleles in both MSH2 and MLH1 could be at increased breast cancer risk. RPA may be modified by genes in the DNA repair pathway, and merit further investigation

Changes in mammographic density over time in breast cancer cases and women at high risk for breast cancer.

High mammographic breast density is one of the strongest intermediate markers of breast cancer risk, and decreases in density over time have been associated with decreases in breast cancer risk. Using repeated measures of mammographic density in a cohort of high-risk women, the Women at Risk (WAR) cohort at Columbia University Medical Center (N=2670), we examined whether changes in prediagnostic mammographic density differed among 85 prospectively-ascertained breast cancer cases and 85 age-matched controls, using a nested case-control design. Median age at first mammogram was 51 years (range, 29-77 years), with a median of 4 years between first and second prediagnostic mammogram (range, 1-15 years). Using linear regression with change in percent density as the outcome, we found that in women who did not go on to be diagnosed with breast cancer, change in percent density decreased as time between first and second mammogram increased (&beta;=-1.62% per year, p=0.004). However, in women who did go on to be diagnosed with breast cancer, there was no overall change in percent density associated with time between first and second mammogram (&beta;=0.29% per year, p=0.61); the change over time was statistically significantly different between cases versus controls (p &lt;0.009). If replicated in larger cohorts, these results suggest that within-individual changes in mammographic density as measured by percent density may be a useful biomarker of breast cancer risk

Supplementary Material for: Understanding Social, Cultural, and Religious Factors Influencing Medical Decision-Making on BRCA1/2 Genetic Testing in the Orthodox Jewish Community

Introduction. Although the prevalence of a pathogenic variant in the BRCA1 and BRCA2 genes is about 1:400 (0.25%) in the general population, the prevalence is as high as 1:40 (2.5%) among the Ashkenazi Jewish population. Despite cost-effective preventive measures for mutation carriers, Orthodox Jews constitute a cultural and religious group that requires different approaches to BRCA1 and BRCA2 genetic testing relative to other groups. This study analyzed a dialogue of key stakeholders and community members to explore factors that influence decision-making about BRCA1 and BRCA2 genetic testing in the New York Orthodox Jewish community. Methods. Qualitative research methods, based on Grounded Theory and Narrative Research, were utilized to analyze the narrative data collected from 49 key stakeholders and community members. A content analysis was conducted to identify themes; inter-rater reliability was 71%. Results. Facilitators of genetic testing were a desire for preventive interventions and education, while barriers to genetic testing included negative emotions, feared impact on family/romantic relationships, cost, and stigma. Views differed on the role of religious leaders and healthcare professionals in medical decision-making. Education, health, and community were discussed as influential factors, and concerns were expressed about disclosure, implementation, and information needs. Conclusion. This study elicited the opinions of Orthodox Jewish women (decision-makers) and key stakeholders (influencers) who play critical roles in the medical decision-making process. The findings have broad implications for engaging community stakeholders within faith-based or culturally distinct groups to ensure better utilization of healthcare services for cancer screening and prevention designed to improve population health