Abstract
Single nucleotide polymorphisms (SNPs) in pathways influencing lymph node (LN) metastasis and estrogen receptor (ER) status in breast cancer may partially explain inter-patient variability in prognosis. We examined 154 SNPs in 12 metastasis-related genes for associations with breast cancer risk, stratified by LN and ER status, in European-American (EA) and African-American (AA) women. Two-thousand six hundred and seventy-one women enrolled in the Women's Circle of Health Study were genotyped. Pathway analyses were conducted using the adaptive rank truncated product (ARTP) method, with p(ARTP) ≤ 0.10 as significant. Multi-allelic risk scores were created for the ARTP-significant gene(s). Single-SNP and risk score associations were modeled using logistic regression, with false discovery rate (FDR) P-value adjustment. Although single-SNP associations were not significant at p(FDR) < 0.05, several genes were significant in the ARTP analyses. In AA women, significant ARTP gene-level associations included CDH1 with LN+ (p(ARTP) = 0.10; multi-allelic OR = 1.13, 95%CI 1.07-1.19, p(FDR) = 0.0003) and SIPA1 with ER- breast cancer (p(ARTP) = 0.10; multi-allelic OR = 1.16, 95%CI 1.02-1.31, p(FDR) = 0.03). In EA women, MTA2 was associated with overall breast cancer risk (p(ARTP) = 0.004), regardless of ER status, and with LN- disease (p(ARTP) = 0.01). Also significant were SATB1 in ER- (p(ARTP) = 0.03; multi-allelic OR = 1.12, 95%CI 1.05-1.20, p(FDR) = 0.003) and KISS1 in LN- (p(ARTP) = 0.10; multi-allelic OR = 1.18, 95%CI 1.08-1.29, p(FDR) = 0.002) analyses. Among LN+ cases, significant ARTP associations were observed for SNAI1, CD82, NME1, and CTNNB1 (multi-allelic OR = 1.09, 95%CI 1.04-1.14, p(FDR) = 0.001). Our findings suggest that variants in several metastasis genes may affect breast cancer risk by LN or ER status, although verification in larger studies is required. © 2016 Wiley Periodicals, Inc.