title: The 6q22.33 locus and breast cancer susceptibility.
abstract: Recently, we identified a novel breast cancer susceptibility locus at 6q22.33 following a genome-wide association study in the Ashkenazi Jewish genetic isolate. To replicate these findings, we did a case-control association analysis on 6q22.33 (rs2180341) in an additional 487 Ashkenazi Jewish breast cancer cases and in an independent non-Jewish, predominantly European American, population of 1,466 breast cancer cases and 1,467 controls. We confirmed the 6q22.33 association with breast cancer risk in the replication cohorts [per-allele odds ratio (OR), 1.18; 95% confidence interval (95% CI), 1.04-1.33; P = 0.0083], with the strongest effect in the aggregate meta-analysis of 3,039 breast cancer cases and 2,616 Ashkenazi Jewish and non-Jewish controls (per-allele OR, 1.24; 95% CI, 1.13-1.36; P = 3.85 x 10(-7)). We also showed that the association was slightly stronger with estrogen receptor-positive tumors (per-allele OR, 1.35; 95% CI, 1.20-1.51; P = 2.2 x 10(-5)) compared with estrogen receptor-negative tumors (per-allele OR, 1.19; 95% CI, 0.97-1.47; P = 0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in breast cancer susceptibility. Due to the stronger association of 6q22.33 with estrogen receptor-positive breast cancer, we examined the effect of candidate genes on estrogen receptor response elements. Upon transfection of overexpressed RNF146 in the MCF-7 breast cancer cell line, we observed diminished expression of an estrogen receptor response element reporter construct. This study confirms the association of 6q22.33 with breast cancer, with slightly stronger effect in estrogen receptor-positive tumors. Further functional studies of candidate genes are in progress, and a large replication analysis is being completed as part of an international consortium.
authors.affiliation: Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. kirchhot@mskcc.org
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhoff
authors.forename: Zhang-qun
authors.initials: ZQ
authors.lastname: Chen
authors.forename: Bert
authors.initials: B
authors.lastname: Gold
authors.forename: Prodipto
authors.initials: P
authors.lastname: Pal
authors.forename: Mia M
authors.initials: MM
authors.lastname: Gaudet
authors.forename: Kristi
authors.initials: K
authors.lastname: Kosarin
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.forename: Peter
authors.initials: P
authors.lastname: Gregersen
authors.forename: Sara
authors.initials: S
authors.lastname: Spencer
authors.forename: Megan
authors.initials: M
authors.lastname: Harlan
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klein
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002896:Chromosomes, Human, Pair 6; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D007585:Jews; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000096:biosynthesis; D012307:Risk Factors; D017421:Sequence Analysis
chemical_list: D011960:Receptors, Estrogen
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