title: No Evidence of BRCA1/2 genomic rearrangements in high-risk French-Canadian breast/ovarian cancer families.
abstract: The discovery of deleterious mutations in the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, has facilitated the identification of individuals at particularly high risk of these diseases. There is a wide variation between populations in the prevalence and related risks of various types of BRCA1/2 mutations, so estimates cannot be extrapolated to Canadians, especially not founder populations such as French- Canadians. Polymerase chain reaction (PCR)-based methods were used to detect the majority of these mutations. These approaches usually failed to detect large DNA rearrangements, which have been claimed to be involved in other populations in 5% to up to 36% of BRCA1-positive families. There is very little information about the contribution of this type of mutation in BRCA2-positive families. To investigate if our available mutation spectrum of BRCA1 and BRCA2 in high-risk French-Canadian breast/ovarian cancer families has been biased by PCR-based direct sequencing methods, we first used Southern blot analysis to test DNA samples from 61 affected/obligate carrier individuals from 58 families in which no BRCA1/2 deleterious mutation was found. Finally, 154 individuals from 135 BRCA1/2 nonconclusive families, including all those tested previously by Southern blot analysis, were tested with the new multiplex ligation probe amplification (MLPA) technique. These approaches failed to detect any rearrangement. Moreover, if the frequency of MLPA-detectable rearrangements in our cohort of 135 BRCA1/2 nonconclusive families was 2.2% or higher, we would have had a 95% or greater chance of observing at least one such rearrangement. As no rearrangements were identified, such large rearrangements must be quite rare in our population.
authors.affiliation: Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec, and Laval University, Québec.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Moisan
authors.forename: Jessyka
authors.initials: J
authors.lastname: Fortin
authors.forename: Martine
authors.initials: M
authors.lastname: Dumont
authors.forename: Carolle
authors.initials: C
authors.lastname: Samson
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: Louise
authors.initials: L
authors.lastname: Provencher
authors.forename: Patricia
authors.initials: P
authors.lastname: Voyer
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
authors.forename: Peter
authors.initials: P
authors.lastname: Bridge
authors.forename: Jacques
authors.initials: J
authors.lastname: Simard
mesh_terms: D015139:Blotting, Southern; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D015336:Molecular Probe Techniques; D010051:Ovarian Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011792:Quebec / Q000453:epidemiology; D012307:Risk Factors