title: Prevalence of BRCA1/2 mutations in sporadic breast/ovarian cancer patients and identification of a novel de novo BRCA1 mutation in a patient diagnosed with late onset breast and ovarian cancer: implications for genetic testing.
abstract: In order to adequately evaluate the clinical relevance of genetic testing in sporadic breast and ovarian cancer patients, we offered comprehensive BRCA1/2 mutation analysis in patients without a family history for the disease. We evaluated the complete coding and splice site regions of BRCA1/2 in 193 sporadic patients. In addition, a de novo mutation was further investigated with ultra deep sequencing and microsatellite marker analysis. In 17 patients (8.8%), a deleterious germline BRCA1/2 mutation was identified. The highest mutation detection ratio (3/7 = 42.9%) was obtained in sporadic patients diagnosed with breast and ovarian cancer after the age of 40. In 21 bilateral breast cancer patients, two mutations were identified (9.5%). Furthermore, 140 sporadic patients with unilateral breast cancer were investigated. Mutations were only identified in patients diagnosed with breast cancer before the age of 40 (12/128 = 9.4% vs. 0/12 with Dx > 40). No mutations were detected in 17 sporadic male breast cancer and 6 ovarian cancer patients. BRCA1 c.3494_3495delTT was identified in a patient diagnosed with breast and ovarian cancer at the age of 52 and 53, respectively, and was proven to have occurred de novo at the paternal allele. Our study shows that the mutation detection probability in specific patient subsets can be significant, therefore mutation analysis should be considered in sporadic patients. As a consequence, a family history for the disease and an early age of onset should not be used as the only criteria for mutation analysis of BRCA1/2. The relatively high mutation detection ratio suggests that the prevalence of BRCA1/2 may be underestimated, especially in sporadic patients who developed breast and ovarian cancer. In addition, although rare, the possibility of a de novo occurrence in a sporadic patient should be considered.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: De Leeneer
authors.forename: Ilse
authors.initials: I
authors.lastname: Coene
authors.forename: Brecht
authors.initials: B
authors.lastname: Crombez
authors.forename: Justine
authors.initials: J
authors.lastname: Simkens
authors.forename: Rudy
authors.initials: R
authors.lastname: Van den Broecke
authors.forename: Alain
authors.initials: A
authors.lastname: Bols
authors.forename: Barbara
authors.initials: B
authors.lastname: Stragier
authors.forename: Ilse
authors.initials: I
authors.lastname: Vanhoutte
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Bruce
authors.initials: B
authors.lastname: Poppe
authors.forename: Kathleen
authors.initials: K
authors.lastname: Claes
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000175:diagnosis* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human