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