Critical windows of susceptibility, genetic loci and breast cancer risk

Abstract

Research suggests that women may be more susceptible to breast cancer risk during critical windows, such as between age at menarche and first childbirth (standardized AFB) and reproductive lifespan defined as the time from menarche to natural menopause excluding anovulatory phases of pregnancy, lactation and oral contraceptive use. Susceptibility during these windows may be influenced by single nucleotide polymorphisms (SNPs). We assessed these hypotheses in 1663 breast cancer cases diagnosed between 1995-2000 and 1508 community controls who participated in a three state, US population-based study. Information on risk factors was collected through structured telephone interviews. DNA samples were collected by mail. In White participants, 13 SNPs identified by genomewide association and follow-up studies were genotyped. Odds ratios (OR) and 95% confidence intervals (CI) adjusted for age and state were calculated using logistic regression. Interaction P-values were obtained by adding a cross-product term to statistical models. Women in the quintile for longest standardized AFB interval compared to the shortest had a 1.4-fold (CI:1.18-1.90) increased breast cancer risk. The risk allele of rs10941679 at 5p12 was suggested to modify the relation between standardized AFB and breast cancer risk (P = 0.04). The reproductive lifespan OR for postmenopausal women was 1.94 (CI:1.32-2.86) comparing the highest and lowest quintiles. No interactions were detected between SNPs and reproductive lifespan (all P > 0.05). Our results confirm that two critical windows are associated with breast cancer risk but that these associations are not materially affected by GWAS-identified SNPs.