Abstract P3-08-02: Common variants at 10p14 and 1p11.2 display heterogeneity in breast cancer associations by E-cadherin tumor tissue expression in two independent datasets

Abstract

Abstract Background: E-cadherin is a tumor suppressor gene involved in cell-cell adhesion, epithelial-to-mesenchymal transitions (EMT) and invasion. Loss of E-cadherin expression is strongly associated with lobular breast cancers, which exhibit single cell patterns of infiltration and are often estrogen receptor positive. We sought to determine if relative risk estimates for 19 established breast cancer susceptibility loci were modified by E-cadherin breast tumor tissue expression. Methods: Case-control analyses included up to 1885 invasive breast cancer cases and 2366 age and site matched controls aged 20–74 years from the Polish Breast Cancer Study (PBCS), 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 × intensity. Tumors having a score of <10 were classified as E-cadherin low and those with a score ≥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. Case-only data from the PBCS (N = 797) and the Study of Epidemiology and Risk Factors in Cancer Heredity, SEARCH (N = 2155) was used in logistic regression models to test for heterogeneity of SNPs by E-cadherin expression. Results: Three SNPs suggested significant heterogeneity by E-cadherin expression in the PBCS: rs2046210 at 6q25.1(ESR1) [per-allele ORs (95% CI); 1.53 (1.19–1.98) for E-cadherin low tumors and 0.99 (0.86–1.14) for E-cadherin high tumors, P-heterogeneity = 0.002]; rs1045485 at 10p14 (CASP8) [per-allele ORs (95% CI); 0.62 (0.41–0.93) for E-cadherin low tumors and 0.98 (0.81–1.18) for E-cadherin high tumors, P-heterogeneity = 0.04]; and rs11249433 at 1p11.2 (NOTCH2/FCGR1B) [per-allele ORs (95% CI); 1.29 (1.02–1.64) for E-cadherin low tumors and 1.01 (0.88–1.15) for E-cadherin high tumors, P-heterogeneity = 0.06]. Combined case-only analysis of PBCS and SEARCH for these three SNPs showed significant heterogeneity by E-cadherin expression for rs11249433 [Interaction OR (95% CI); 1.19 (1.05–1.36), P-heterogeneity = 0.007] and rs1045485 [Interaction OR (95% CI); 0.69 (0.53–0.90), P-heterogeneity = 0.007]. The association with rs2046210 [Interaction OR (95% CI); 1.12 (0.61–2.03), P-heterogeneity = 0.73] did not remain significant in combined analyses. Conclusion: Our findings provide evidence that associations for breast cancer susceptibility loci vary by E-cadherin tumor tissue expression, which has not been described previously. Specifically, our results suggest that the genetic markers rs11249433 and rs1045485 may preferentially modify risk for tumors with low or absent E-cadherin expression in two independent data sets. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-02.