title: Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer.
abstract: Few studies have reported on the comprehensive BRCA1/2 mutation analyses of hereditary breast cancer (HBC) families of French Canadian descent. Here we report the investigation of 82 families with at least 3 cases of breast cancer evaluated for mutations by DNA sequencing and/or multiplex ligation-dependent probe amplification (MLPA) assay. DNA sequencing identified pathogenic mutations in 37 (45.1%) families, of which 70.2% were one of three recurring mutations (BRCA1:R1443X, BRCA2:8765delAG, and BRCA2:E1953X) frequently reported in this founder population; and variants of uncertain clinical significance in 7 (8.5%) families of which two harbored BRCA2:E3002K. MLPA analysis of the 38 DNA sequence-negative families did not reveal any large rearrangements in BRCA1/2. A phenotypic characterization of the cancer families based on pathogenic mutation status revealed that there were significantly fewer very young age at diagnosis breast cancer cases (<36 years) in mutation-negative families (5.9%, 9 of 153) than in BRCA1 (22.8%, 13 of 57; P = 0.0003) or BRCA2 (22.9%, 27 of 118; P < 1× 10E5) mutation-positive families. There were significantly more mutation-positive families (29 of 36, 80.6%) with a very young age of onset of breast cancer case than those that did not (8 of 39, 20.5%) (P < 10E6). The comprehensive mutation analysis of BRCA1/2 suggests that genomic rearrangements are unlikely to account for sequence-negative HBC families and affirms that the presence of a very young age of diagnosis of breast cancer is strongly predictive of mutation carrier status of French Canadian HBC families.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Luca
authors.initials: L
authors.lastname: Cavallone
authors.forename: Suzanna L
authors.initials: SL
authors.lastname: Arcand
authors.forename: Christine M
authors.initials: CM
authors.lastname: Maugard
authors.forename: Serge
authors.initials: S
authors.lastname: Nolet
authors.forename: Louis A
authors.initials: LA
authors.lastname: Gaboury
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Parviz
authors.initials: P
authors.lastname: Ghadirian
authors.forename: Diane
authors.initials: D
authors.lastname: Provencher
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Tonin
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D002170:Canada / Q000453:epidemiology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004273:DNA, Neoplasm