title: Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers.
abstract: Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.25-1.92, p = 6.0 × 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 % CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Stevens
authors.forename: Xianshu
authors.initials: X
authors.lastname: Wang
authors.forename: Zachary
authors.initials: Z
authors.lastname: Fredericksen
authors.forename: Vernon S
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Mark H
authors.initials: MH
authors.lastname: Greene
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Mads
authors.initials: M
authors.lastname: Thomassen
authors.forename: Maria
authors.initials: M
authors.lastname: Caligo
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Anna
authors.initials: A
authors.lastname: Jakubowska
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: Melissa
authors.initials: M
authors.lastname: Southey
authors.forename: Saundra S
authors.initials: SS
authors.lastname: Buys
authors.forename: Christian F
authors.initials: CF
authors.lastname: Singer
authors.forename: Thomas V O
authors.initials: TV
authors.lastname: Hansen
authors.forename: Adalgeir
authors.initials: A
authors.lastname: Arason
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Marion
authors.initials: M
authors.lastname: Piedmonte
authors.forename: Marco
authors.initials: M
authors.lastname: Montagna
authors.forename: Evgeny
authors.initials: E
authors.lastname: Imyanitov
authors.forename: Laima
authors.initials: L
authors.lastname: Tihomirova
authors.forename: Lara
authors.initials: L
authors.lastname: Sucheston
authors.forename: Mary
authors.initials: M
authors.lastname: Beattie
authors.forename: Susan L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: Csilla I
authors.initials: CI
authors.lastname: Szabo
authors.forename: Jacques
authors.initials: J
authors.lastname: Simard
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: Sue
authors.initials: S
authors.lastname: Healey
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: Antonis C
authors.initials: AC
authors.lastname: Antoniou
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein