Abstract 2796: Single nucleotide variants in metastasis-related genes are associated with breast cancer risk, by lymph node involvement and ER status, in women with European and African ancestry
Authors: Roberts Michelle , Sucheston-Campbell Lara E. , Zirpoli Gary R. , Bandera Elisa V. , Ambrosone Christine B. , Yao Song 
Published: August 2015

Inherited genetic variation may partially explain inter-patient variability in prognosis by influencing lymph node involvement and estrogen receptor (ER) status in breast cancer patients, which may differ by ancestral background. We examined 154 tagging single nucleotide polymorphisms (SNPs) in 12 metastasis-related genes (BRMS1, CDH1, CD82, CTNNB1, KISS1, MTA1, MTA2, MTA3, NME1, SATB1, SIPA1, SNAI1) for associations with risk of breast cancer, stratified by lymph node and ER status.

Genotyping was performed in 2,671 European-American (EA) and African-American (AA) women enrolled in the Women's Circle of Health case-control study (WCHS) using Illumina GoldenGate assays. Single-SNP and haplotype associations were analyzed using logistic regression. Pathway analyses were conducted using the adaptive rank truncated product (ARTP) method, with p≤0.10 as significant. To estimate risk, multiallelic scores were created using the SNPs in the significant gene(s). All models were adjusted for age and ancestry; multiallelic score models also included demographic covariates. P-values were corrected using the false discovery rate (FDR) method.

Single-SNP and haplotype associations were not significant after FDR adjustment at p&lt;0.05. In AA women, significant ARTP gene-level associations included CDH1 with risk of lymph node positive breast cancer (p = 0.10) and SIPA1 with ER negative breast cancer in both case-control (p = 0.10) and case-case (p = 0.09) analyses. Multiallelic scores computed from SNPs in CDH1 and SIPA1 were associated with node positive (OR = 1.13, 95% CI 1.07-1.19, pFDR = 0.0003) and ER negative (OR = 1.16, 95% CI 1.02-1.31, pFDR = 0.03) breast cancer, respectively.

In EA women, MTA2 was associated with overall risk of breast cancer at the ARTP gene-level (p = 0.004), regardless of ER status, and with node negative breast cancer (p = 0.01). SATB1 and KISS1 were also significant in ER negative (ARTP gene-level p = 0.03) and node negative (ARTP gene-level p = 0.10) analyses, respectively. Among EA lymph node positive cases, significant ARTP gene-level associations were observed for SNAI1 (p = 0.10), CD82 (p = 0.05), NME1 (p = 0.10), and CTNNB1 (p = 0.09). The SNAI1-CD82-NME1-CTNNB1 multiallelic risk score was associated with node positive (OR = 1.09, 95% CI 1.04-1.14, pFDR = 0.001) and the MTA2-KISS1 score with node negative breast cancer (OR = 1.18, 95% CI 1.08-1.29, pFDR = 0.002). Stratified by ER status, the MTA2 score was associated with ER positive (OR = 1.16, 95% CI 1.05-1.30, pFDR = 0.01) and the MTA2-SATB1 score with ER negative breast cancer (OR = 1.12, 95% CI 1.05-1.20, pFDR = 0.003).

Our findings suggest that genetic variants in several metastasis genes may affect risk of breast cancer by lymph node or ER status. These results require verification in larger studies, particularly those that can evaluate long-term prognosis.

Citation Format: Michelle Roberts, Lara E. Sucheston-Campbell, Gary R. Zirpoli, Elisa V. Bandera, Christine B. Ambrosone, Song Yao. Single nucleotide variants in metastasis-related genes are associated with breast cancer risk, by lymph node involvement and ER status, in women with European and African ancestry. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2796. doi:10.1158/1538-7445.AM2015-2796