title: Germline RAP80 mutations and susceptibility to breast cancer.
abstract: Most of the breast cancer susceptibility genes identified to date are involved in DNA repair, including BRCA1, BRCA2, PALB2, CHEK2 and BRIP1. RAP80 works upstream of BRCA1 and is essential for the localization of BRCA1 to the site of damaged DNA. To investigate whether or not RAP80 is also a breast cancer susceptibility gene, we sequenced the entire exonic regions of RAP80 in the germline DNA of 152 women with familial breast cancer, who were previously found to be negative for BRCA1 and BRCA2 mutations. No truncating mutation was identified. Eleven potentially deleterious RAP80 variants were identified; these 11 variants were genotyped in 424 more familial cases and in 726 healthy controls. Three novel p.Ala342Thr, p.Met353Thr and p.Tyr575Asp rare missense variants and a novel haplotype composed of two variants in the CpG island (c.-24149G > T and c.-24001A > G) and a variant in the 5'UTR (c.-8A > G) and a variant in the 3'UTR (c.*27A > C) were detected in 26 of 571 (4.6%) individuals with familial breast cancer, compared to 14 of 725 (1.9%) controls (P = 0.01; OR = 2.4, 95% CI = 1.2-5.1). In summary, we did not find truncating mutations of the RAP80 gene to be a cause of familial breast cancer. A novel RAP80 haplotype or rare missense mutations may be associated with a modest increased risk of breast cancer, but this observation needs to be confirmed by additional studies.
authors.affiliation: Women's College Research Institute, University of Toronto, 790 Bay Street, 7th floor, Toronto, ON, Canada.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Akbari
authors.forename: Parviz
authors.initials: P
authors.lastname: Ghadirian
authors.forename: Andre
authors.initials: A
authors.lastname: Robidoux
authors.forename: Maryam
authors.initials: M
authors.lastname: Foumani
authors.forename: Yulong
authors.initials: Y
authors.lastname: Sun
authors.forename: Robert
authors.initials: R
authors.lastname: Royer
authors.forename: Inuk
authors.initials: I
authors.lastname: Zandvakili
authors.forename: Henry
authors.initials: H
authors.lastname: Lynch
authors.forename: Steven A
authors.initials: SA
authors.lastname: Narod
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D005787:Gene Frequency; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes / Q000235:genetics; D056488:Histone Chaperones; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D009386:Neoplastic Syndromes, Hereditary / Q000453:epidemiology / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D018389:Codon, Nonsense; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D009687:Nuclear Proteins; C466234:UIMC1 protein, human