Ages at menarche- and menopause-related genetic variants in relation to terminal duct lobular unit involution in normal breast tissue

Abstract

Purpose Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. Methods We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. Results Fourteen percent of evaluated SNPs (8 SNPs) were associated with TDLU counts at p<0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50% that were either significantly or nonsignficantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among 10 SNPs that were statistically significantly associated with at least one TDLU involution measure (p<0.05), seven SNPs (rs466639: RXRG; rs2243803: SLC14A2; rs2292573: GAB2; rs6438424: 3q13.32; rs7606918: METAP1D; rs11668344: TMEM150B; rs1635501: EXO1) were associated in the consistent directions. Conclusions Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results.

Association of genetic polymorphisms with age at menarche in Russian women

“…Elks et al (Elks et al, 2010) also suggested contribution of this SNP to height based on the GIANT consortium data. Oh et al (Oh et al, 2016) reported association of rs6438424 with the breast tissue development.…”

Genetic variations, reproductive aging, and breast cancer risk in African American and European American women: The Women's Circle of Health Study

“…However, the biological impact of the SNP on gene expression and the mechanism of RXRG in regulating reproductive aging, remain unclear. In a recent study, rs466639 was associated with involution of terminal duct lobular unit (TDLU), the milk-producing structures of the breast[ 48 ]. The variant T allele associated with earlier AM was also associated with a higher count of TDLU, which is a recognized risk factor for breast cancer.…”

Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast

“…Because SNPs examined in this analysis are well‐established breast cancer susceptibility loci, we used a threshold of p < 0.05 to define significant associations. Since our power to test for individual associations was limited, we also tested for enrichment of associations between SNPs and measures of TDLU involution . We did this using binomial tests in two ways: ( i ) comparing the proportion of the SNP associations (regardless of statistical significance) in the direction consistent with our expectation (RR > 1.0) based on the relationship of the SNPs with breast cancer to 50%, which is what would have been expected by chance; and ( ii ) comparing the proportion of SNPs with significant associations to 5%, which is expected by chance alone.…”