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Title: Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects.
Authors: Nyante SJ,  Gammon MD,  Kaufman JS,  Bensen JT,  Lin DY,  Barnholtz-Sloan JS,  Hu Y,  He Q,  Luo J,  Millikan RC
Journal: Cancer Causes Control
Date: 2015 Jan
Branches: HREB
PubMed ID: 25421376
PMC ID: PMC4291841
Abstract: PURPOSE: To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina. METHODS: Cases (n=1,972) were women 20-74years old and diagnosed with breast cancer between 1993 and 2001. Population-based controls (n=1,776) were frequency matched to cases by age and race. A total of 195 SNPs were genotyped, and linkage disequilibrium was evaluated using the r (2) statistic. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations with breast cancer overall and by molecular subtype were estimated using logistic regression. Monte Carlo methods were used to control for multiple comparisons; two-sided p values <3.3נ10(-4) were statistically significant. Heterogeneity tests comparing the two most common subtypes, luminal A (n=679) and basal-like (n=200), were based on the Wald statistic. RESULTS: ESR1 rs6914211 (AA vs. AT+TT, OR 2.24, 95% CI 1.51-3.33), ESR1 rs985191 (CC vs. AA, OR 2.11, 95% CI 1.43-3.13), and PGR rs1824128 (TT+GT vs. GG, OR 1.33, 95% CI 1.14-1.55) were associated with risk after accounting for multiple comparisons. Rs6914211 and rs985191 were in strong linkage disequilibrium among controls (African-Americans r (2)=0.70; whites r (2)=0.95). There was no evidence of heterogeneity between luminal A and basal-like subtypes, and the three SNPs were also associated with elevated risk of the less common luminal B, HER2+/ER-, and unclassified subtypes. CONCLUSIONS: ESR1 and PGR SNPs were associated with risk, but lack of heterogeneity between subtypes suggests variants in hormone-related genes may play similar roles in the etiology of breast cancer molecular subtypes.