title: Germline mutations in the breast cancer susceptibility gene PTEN are rare in high-risk non-BRCA1/2 French Canadian breast cancer families.
abstract: Cowden syndrome is a disease associated with an increase in breast cancer susceptibility. Alleles in PTEN and other breast cancer susceptibility genes would be responsible for approximately 25% of the familial component of breast cancer risk, BRCA1 and BRCA2 being the two major genes responsible for this inherited risk. In order to evaluate the proportion of high-risk French Canadian non-BRCA1/BRCA2 breast/ovarian cancer families potentially harboring a PTEN germline mutation, the whole coding and flanking intronic sequences were analyzed in a series of 98 breast cancer cases. Although no germline mutation has been identified in the coding region, our study led to the identification of four intronic variants. Further investigations were performed to analyze the effect of these variants, alone and/or in combination, on splicing and PTEN protein levels. Despite suggestive evidence emerging from in silico analyses, the presence of these intronic variants do not seem to alter RNA splicing or PTEN protein levels. In addition, as loss of PTEN or part of it has been reported, Western blot analysis has also been performed. No major deletion could be identified in our cohort. Therefore, assuming a Poisson distribution for the frequency of deleterious mutation in our cohort, if the frequency of such deleterious mutation was 2%, we would have had a 90% or greater chance of observing at least one such mutation. These results suggest that PTEN germline mutations are rare and are unlikely to account for a significant proportion of familial breast cancer cases in the French Canadian population.
authors.affiliation: Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, CHUQ, Pavillon CHUL, Laval University, Quebec City, QC, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Guénard
authors.forename: Yvan
authors.initials: Y
authors.lastname: Labrie
authors.forename: Geneviève
authors.initials: G
authors.lastname: Ouellette
authors.forename: Charles Joly
authors.initials: CJ
authors.lastname: Beauparlant
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: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D002170:Canada / Q000208:ethnology; D005602:France / Q000208:ethnology; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D012260:Ribonucleases / Q000378:metabolism; D012307:Risk Factors; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D012260:Ribonucleases; D051059:PTEN Phosphohydrolase