Germline mutations in the breast cancer susceptibility gene PTEN are rare in high-risk non-BRCA1/2 French Canadian breast cancer families.
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.
Guénard
Frédéric
F
Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, CHUQ, Pavillon CHUL, Laval University, Quebec City, QC, Canada.
Labrie
Yvan
Y
Ouellette
Geneviève
G
Beauparlant
Charles Joly
CJ
Bessette
Paul
P
Chiquette
Jocelyne
J
Laframboise
Rachel
R
Lépine
Jean
J
Lespérance
Bernard
B
Pichette
Roxane
R
Plante
Marie
M
Durocher
Francine
F
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
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D012260:Ribonucleases; D051059:PTEN Phosphohydrolase