title: Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.
abstract: The main focus of this German-wide multi-center study was to establish a BRCA1/2 mutation profile and to determine family types with high frequencies of mutations in these genes. In a comprehensive study, the entire coding sequences of the breast cancer genes BRCA1 and BRCA2 were analyzed in 989 unrelated patients from German breast/ovarian cancer families. A total of 77 BRCA1 and 63 BRCA2 distinct deleterious mutations were found in 302 patients. More than (1/3) of these mutations are novel and might be specific for the German population. Eighteen common mutations were found in 68% of cases in BRCA1 and 13 recurrent mutations in 44% of cases in BRCA2, facilitating prescreening approaches. Haplotype analysis indicate that 14 out of 20 recurrent mutations are likely originating from a common founder. An additional 50 different rare sequence variants with unknown relevance for tumorigenesis were found in 72 families. Correlation of BRCA1/BRCA2 detection rates with family history identified families with both breast and ovarian cancer to be at highest risk for BRCA1/BRCA2 mutations (43% and 10%, respectively), followed by families with at least 2 premenopausal cases of breast cancer (24% BRCA1 and 13% BRCA2 mutations). These data provide strong evidence for further predisposing genes in the German population. In breast cancer families with 2 or 3 affected females but only a single or no premenopausal case, mutations were detected with low frequencies (about 10% or less for both genes). The decision for or against molecular diagnosis is now aided by considering the expected mutation detection rates that greatly depend on family history and structure.
authors.affiliation: Department of Medical Genetics, Ludwig-Maximilians University, Munich, Germany. alfons@pedgen.med.uni-muenchen.de
authors.forename: A
authors.initials: A
authors.lastname: Meindl
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D018703:Founder Effect; D016368:Frameshift Mutation; D005787:Gene Frequency; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005858:Germany / Q000453:epidemiology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009378:Neoplasms, Multiple Primary / Q000453:epidemiology / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000453:epidemiology / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics; D015995:Prevalence; D012326:RNA Splicing / Q000235:genetics; D012307:Risk Factors; D017384:Sequence Deletion
chemical_list: D004273:DNA, Neoplasm