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.

BRCA1 and BRCA2 germline mutations in Korean ovarian cancer patients

“…BRCA1 and BRCA2 germline mutations were detected in 33% (13/40) of the epithelial ovarian cancer patients with a strong family history. Our results are consistent with the previous reports (de la Hoya et al 2002;Martin et al 2001;Meindl 2002;Menkiszak et al 2003;Rashid et al 2006;Sekine et al 2001) involving other ethnicities (Table 5).…”

“…Direct sequencing used in this study was nevertheless useful to detect new and rare mutations. Meindl (2002) G e r m a n y a 26% (130/500) Rashid et al (2006) P a k i s t a n a 17% (30/176) Rashid et al (2006) P a k i s t a n b 12% (3/25) Therefore, genetic testing of BRCA1 and BRCA2 using full sequencing in Korean patients may be beneWcial until the identiWcation of highly recurrent founder mutations speciWc to Koreans. Site-speciWc ovarian cancer is currently considered a variant of hereditary breast ovarian cancer syndrome, rather than a speciWc syndrome, because no susceptible gene has been identiWed speciWcally for ovarian cancer (Russo et al 2009).…”

Women’s Experiences of Undergoing BRCA1 and BRCA2 Testing: Organisation of the German Hereditary Breast and Ovarian Cancer Consortium Survey and Preliminary Data from Münster

“…Large deletions cannot be detected. The results have provided information about the prevalence of specific mutations in Germany [4]. 18 common mutations in BRCA1 were found in 68% of cases and 13 recurrent mutations in BRCA2 in 44% of cases.…”

Polymorphisms in BRCA2 resulting in aberrant codon-usage and their analysis on familial breast cancer risk

“…The breast cancer cases are comprised of unrelated women that had been tested BRCA1/2 mutation-negative by applying the denaturing high performance liquid chromatography (DHPLC) method on all exons, followed by direct sequencing of conspicuous exons [8]. The BC samples were collected during the years 1997-2007 by three centres of the German Consortium for Hereditary Breast and Ovarian Cancer (centres of Heidelberg, Cologne and Munich, see authors' affiliations).…”

“…Among them, the breast cancer 1 gene (BRCA1) and breast cancer 2 gene (BRCA2) are the most important ones. Mutations in these genes confer a high-penetrance and account for about 5-30% of familial breast cancer cases [8][9][10]. Missense mutations, intronic variants and in-frame deletions or insertions in either BRCA1 or BRCA2 confer a lifetime risk of breast cancer from 60 to 85% [11][12][13][14].…”