Breast cancer susceptibility loci in association with age at menarche, age at natural menopause and the reproductive lifespan Free

Purpose: Genome wide association studies have identified common single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Many of these SNPs have an unknown biologic significance. Hormonal risk factors may mediate the relationships between these loci and breast cancer risk. We explored the relation between breast cancer susceptibility loci and menstrual factors using data from two population-based studies. Methods: In the first dataset, composed of 1328 women ages 20–74 years without a breast cancer diagnosis who participated in an established population-based study conducted in three U.S. states, we used linear regression to assess the associations between 13 previously-identified breast cancer loci with age at menarche, age at natural menopause and the reproductive lifespan. The reproductive lifespan is defined as the time between age at menarche and age at natural menopause, excluding time for pregnancy, oral contraceptive use and lactation. A polygenic risk score created as the sum of the number of risk allele copies in the SNPs was also evaluated for an association with menstrual traits. Significant results were then evaluated in the second dataset comprised of 1353 women ages 43–86 years recruited as part of a cohort study based in Beaver Dam, WI. Results: Polygenic score and 13 loci were not associated with either age at menarche or reproductive lifespan. Two SNPs were associated with age at natural menopause; each increase in the number of copies of the minor allele (A) of rs17468277 (CASP8) was associated with a 1.12 year decrease in age at natural menopause (p = 0.02). The minor allele (G) of SNP rs10941679 (5p12) (p = 0.01) was associated with a 1.01 year increase in age at natural menopause, although these results were not replicated in the follow-up study (p = 0.14 and 0.98, respectively). Conclusions: We did not find evidence to support the hypothesis that breast cancer susceptibility loci are related to menstrual factors.