title: Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing.
abstract: Index cases from a clinically relevant cohort of 102 Spanish families with at least 3 cases of breast and/or ovarian cancer (at least 1 case diagnosed before age 50) in the same lineage were screened for germline mutations in the entire coding sequence and intron boundaries of the breast cancer susceptibility genes BRCA1 and BRCA2. Overall, the prevalence of mutations was 43% in female breast/ovarian cancer families, 15% in female breast cancer families and 100% in male breast cancer families. Three recurrent mutations (185delAG, 589delCT and A1708E) explained 63% of BRCA1-related families. Early age at diagnosis of breast cancer, ovarian cancer, bilateral breast cancer, concomitant breast/ovarian cancer in a single patient and prostate cancer but not unilateral breast cancer were associated with BRCA1 and BRCA2 mutations. Male breast cancer was associated with BRCA2 mutations. The presence of male breast cancer was the only cancer phenotype that distinguished BRCA2- from BRCA1-related families. We have developed a logistic regression model for predicting the probability of harbouring a mutation in either BRCA1 or BRCA2 as a function of the cancer phenotype present in the family. The predictive positive and negative values of this model were 77.4% and 79%, respectively (probability cutoff of 30%). The findings of our work may be a useful tool for increasing the cost-effectiveness of genetic testing in familial cancer clinics.
authors.affiliation: Laboratory of Molecular Oncology, Hospital Universitario San Carlos, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: de la Hoya
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.forename: Javier
authors.initials: J
authors.lastname: Godino
authors.forename: Sara
authors.initials: S
authors.lastname: Sulleiro
authors.forename: Alicia
authors.initials: A
authors.lastname: Tosar
authors.forename: Pedro
authors.initials: P
authors.lastname: Perez-Segura
authors.forename: Cristina
authors.initials: C
authors.lastname: Fernandez
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodríguez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Díaz-Rubio
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
mesh_terms: D017668:Age of Onset; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D003362:Cost-Benefit Analysis; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D005787:Gene Frequency; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000191:economics; D006801:Humans; D008297:Male; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000453:epidemiology / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics; D011174:Portugal / Q000453:epidemiology; D015995:Prevalence; D012326:RNA Splicing / Q000235:genetics; D017384:Sequence Deletion; D013030:Spain / Q000453:epidemiology
chemical_list: D004273:DNA, Neoplasm