Abstract LB-336: Association of variant rs2046210 at 6q25.1 (ESR1) with breast cancer risk suggests heterogeneity by E-cadherin tumor tissue expression
Authors: Horne Hisani N. , Sherman Mark E. , Yang Xiaohong R. , Garcia-Closas Montserrat , Lissowska Jolanta , Brinton Louise A. , Chanock Stephen J. , Figueroa Jonine D. 
Published: August 2012

Background: E-cadherin is a cell-cell adhesion protein that functions as a cancer tumor suppressor gene based on in vitro and in vivo evidence showing that loss of this gene can lead to tumor progression and invasion. E-cadherin loss is strongly associated with breast tumors of lobular histology, which are more likely to be estrogen receptor-alpha (ESR1) positive and more frequently metastasize to the gastrointestinal tract and ovary compared to ductal tumors. We sought to determine if relative risk estimates for 19 established breast cancer susceptibility loci were modified by E-cadherin expression levels and tumor histology. Methods: Analyses included up to 1885 invasive breast cancer cases and 2366 age and site matched controls aged 20-74 years, from a population-based case-control study conducted in Poland from 2000-2003. Genotyping of the 19 single nucleotide polymorphisms (SNPs) was performed using TaqMan assays. Tissue expression of E-cadherin was assessed using immunohistochemical (IHC) staining of tissue microarrays and IHC results were scored as the product of percent positive tumor cells x intensity. Tumors with a score of &lt;10 were classified as E-cadherin low and scores ≥10 as E-cadherin high. Polytomous logistic regression models adjusted for age and study site were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for each breast cancer subtype, defined by E-cadherin expression levels, compared to controls. Logistic regression models restricted to cases were used to test for heterogeneity by tumor characteristics. Results: We observed significant associations with breast cancer risk overall for the following SNPs: 1p11.2 (NOTCH2/FCGR1B), 2q35 (TNP1/IGFBP5/IGFBP2/TNS1), 6q25.1 (ESR1), 8q24 (FAM84B/c-MYC/POU5F1P1), 9p21 (CDKN2B), 10p14 (CASP8), 10q21.2 (ZNF365), 10q26 (FGFR2), 11q13 (ORAOV1), 14q24.1 (RAD51L1) and two SNPs at 5p12 (MRPS30/FGFR10). One SNP rs2046210 at 6q25.1 (ESR1) displayed significant heterogeneity by E-cadherin expression after Bonferroni adjustment (Pheterogeneity= 0.002), showing stronger associations with breast tumors that had low E-cadherin expression levels compared to high. The estimated OR per A-allele for E-cadherin low (N = 136) tumors was 1.53 (95% CI = 1.19-1.98) and 0.99 for E-cadherin high tumors (N = 566) (95% CI = 0.86-1.14). These differences were not explained by lobular/ductal histology [per A-allele ORs (95% CI) for E-cadherin low lobular = 1.60 (1.15-2.22) and, for E-cadherin low ductal = 1.45 (0.88-2.40)] or ER status. Conclusions: Our data suggest that associations for breast cancer susceptibility loci vary by E-cadherin expression in breast cancer tumor tissues. Specifically, our results suggest that the genetic marker rs2046210 SNP at 6q25.1 may preferentially increase risk for tumors with low or absent E-cadherin expression, which requires replication in other datasets.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-336. doi:1538-7445.AM2012-LB-336