title: Genetic variants and haplotype analyses of the ZBRK1/ZNF350 gene in high-risk non BRCA1/2 French Canadian breast and ovarian cancer families.
abstract: Our current understanding of breast cancer susceptibility involves mutations in the 2 major genes BRCA1 and BRCA2, found in about 25% of high-risk families, as well as few other low penetrance genes such as ATM and CHEK2. Approximately two-thirds of the multiple cases families remain to be explained by mutations in still unknown genes. In a candidate gene approach to identify new genes potentially involved in breast cancer susceptibility, we analyzed genomic variants in the ZBRK1 gene, a co-repressor implicated in BRCA1-mediated repression of GADD45. Direct sequencing of ZBRK1 entire coding region in affected breast cancer individuals from 97 high-risk French Canadian breast/ovarian cancer families and 94 healthy controls led to the identification of 18 genomic variants. Haplotype analyses, using PHASE, COCAPHASE and HaploStats programs, put in evidence 3 specific haplotypes which could potentially modulate breast cancer risk, and among which 2 that are associated with a potential protective effect (p = 0.01135 and p = 0.00268), while another haplotype is over-represented in the case group (p = 0.00143). Further analyses of these haplotypes indicated that a strong component of the observed difference between both groups emerge from the first 5 variants (out of 12 used for haplotype determination). The present study also permitted to determine a set of tagging SNPs that could be useful for subsequent analyses in large scale association studies. Additional studies in large cohorts and other populations will however be needed to further evaluate if common and/or rare ZBRK1 sequence variants and haplotypes could be associated with a modest/intermediate breast cancer risk.
authors.affiliation: Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Desjardins
authors.forename: Pascal
authors.initials: P
authors.lastname: Belleau
authors.forename: Yvan
authors.initials: Y
authors.lastname: Labrie
authors.forename: Geneviève
authors.initials: G
authors.lastname: Ouellette
authors.forename: Paul
authors.initials: P
authors.lastname: Bessette
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Chiquette
authors.forename: Rachel
authors.initials: R
authors.lastname: Laframboise
authors.forename: Jean
authors.initials: J
authors.lastname: Lépine
authors.forename: Bernard
authors.initials: B
authors.lastname: Lespérance
authors.forename: Roxane
authors.initials: R
authors.lastname: Pichette
authors.forename: Marie
authors.initials: M
authors.lastname: Plante
authors.forename: Francine
authors.initials: F
authors.lastname: Durocher
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D044465:White People
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C422407:ZNF350 protein, human