title: Evaluation of the contribution of the three breast cancer susceptibility genes CHEK2, STK11, and PALB2 in non-BRCA1/2 French Canadian families with high risk of breast cancer.
abstract: Inactivating mutations of the CHEK2 and STK11 genes are responsible for Li-Fraumeni and Peutz-Jeghers syndrome, respectively, both autosomal dominant syndromes associated with an increased risk of breast cancer. The PALB2/FANCN gene encodes a nuclear partner of BRCA2 and acts as a linker between BRCA1 and BRCA2. Monoallelic PALB2 truncating mutations were shown to confer higher risk of breast cancer. To evaluate the proportion of French Canadian non-BRCA1/BRCA2 families with high risk of breast cancer potentially harboring alterations in these three breast cancer susceptibility genes, the whole coding and flanking intronic sequences were analyzed in a series of 96 high-risk breast cancer individuals. Despite no PALB2 deleterious truncating mutations being identified, the c.1100delC breast-cancer-associated CHEK2 mutation and a STK11 mutation reported to be the causative mutation in a Peutz-Jeghers family were identified. This extensive analysis also led to the identification of several variants in these genes. Ascertainment of allele frequency of these variants in a cohort of 96 healthy unrelated women suggests a difference in allele frequency for two STK11 intronic variants. In addition, large genomic rearrangements in both STK11 and PALB2 were also examined. Our analysis led to the conclusion that CHEK2, STK11, and PALB2 mutations or large genomic rearrangements of either STK11 or PALB2 are rare, and do not contribute to a substantial fraction of breast cancer susceptibility in high-risk French Canadian breast cancer families.
authors: Cancer Genomics Laboratory, Department of Molecular Medicine, Laval University, Québec City, Québec, Canada.
authors: Frédéric
authors: F
authors: Guénard
authors: Christopher St-Laurent
authors: CS
authors: Pedneault
authors: Geneviève
authors: G
authors: Ouellette
authors: Yvan
authors: Y
authors: Labrie
authors: Jacques
authors: J
authors: Simard
authors: Francine
authors: F
authors: Durocher
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D002170:Canada; D002277:Carcinoma / Q000235:genetics*; D064447:Checkpoint Kinase 2; D004252:DNA Mutational Analysis; D005190:Family; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D011792:Quebec; D012306:Risk; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases