Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany

Abstract

Breast cancer is the most common malignancy affecting women world wide.1 Approximately 1 in 10 women will develop breast cancer during their life time 2 and 5-10% of all breast cancers, in particular those with an early age of onset, are the result of a genetic predisposition owing to the inheritance of a dominant susceptibility gene(s).In the context of high risk families, one important gene is the BRCA2 gene located on chromosome 13q12-13. BRCA2 was localised to chromosome 13q by linkage analysis in 1994 3 and cloned in 1995.4 5 To date, more than 250 BRCA2 germline mutations have been identified in breast/ovarian cancer families. 6 The majority of these mutations are nonsense mutations or frameshift mutations that generate premature termination codons.7 Recent studies on highly selected families with at least four cases of breast cancer suggest that BRCA2 accounts for the majority of breast cancer families where males as well as females are affected, for about one third of the families with female breast cancer alone, and only for a few families containing multiple cases of breast and ovarian cancer.8 BRCA2 encodes a nuclear protein of 3418 amino acid residues that is postulated to play a role in the regulation of gene expression 9 and in DNA double strand break repair and homologous recombination. 10Estimates of the cumulative breast cancer risks by the age of 70 in BRCA2 mutation carriers vary from 37-85% 8 11 and the cumulative ovarian cancer risks from 16-27%.8 12 There is evidence for an increased risk of several other cancers including prostate cancer, pancreatic cancer, gall bladder and bile duct cancer, stomach cancer, and malignant melanoma.13 Analyses of BRCA2 mutation data have provided evidence that the risks of breast cancer and ovarian cancer are related to the position of the mutation. Truncating mutations in families with the highest risk of ovarian cancer relative to breast cancer are clustered in the Ovarian Cancer Cluster Region (OCCR) in exon 11. 14 15 In Germany, 18% of the breast/ovarian cancer families are the result of BRCA1 germline mutations. [16][17][18][19] To determine the contribution of BRCA2 to hereditary breast/ovarian cancer, we have performed a systematic study of the BRCA2 gene in a series of 68 BRCA1 negative breast/ovarian cancer families by using a combination of single strand conformational polymorphism analysis (SSCP) and the protein truncation test (PTT) followed by DNA sequencing analysis. METHODS FamiliesPatients were identified through an ongoing research family study of hereditary breast/ovarian cancer recruiting families from all over Germany. Families containing three or more members affected with breast/ovarian cancer with at least two breast cancer cases diagnosed under the age of 60 years and ovarian cancer diagnosed at any age were ascertained through gynaecologists or in response to press publicity in Germany. Each pedigree was extended through an index case and available related family members. All participants gave informed consent and blood samples. B...

Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer

“…The absence of any index cases harboring such complex rearrangements could be due to selection criteria, as BRCA1 mutations are more frequently observed in HBOC than HBC families [12][13][14]. Although a recent review of 54 French Canadian HBOC families from our group did not include an analysis of large deletions [10], a further investigation by MLPA analysis of the 9 mutation-negative HBOC families with serous histopathological subtype ovarian cancers did not reveal any evidence for missed BRCA1/2 mutations (unpublished results).…”

“…The frequency of mutation-positive HBOC families increased with the number of ovarian cancer cases, particularly if they had a serous histopathological subtype of ovarian cancer [10,11]. Independent studies of French Canadian cancer families [12] as well as of other populations of European descent [11,13,14], also reported a higher proportion of mutationpositive HBOC families than HBC families. These findings support the notion that the majority of HBOC families are accounted for by BRCA1 and BRCA2 mutations and have rationalized the exclusion of cancer families with ovarian cancer cases in studies aimed at finding additional alleles that confer a high risk for breast cancer [15][16][17].…”

High proportion of BRCA1/2 founder mutations in Hispanic breast/ovarian cancer families from Colombia

“…SSCP and PTT analysis was performed as previously described [16,17]. DHPLC analysis was performed using the WAVE system (Transgenomics, Omaha, NE, USA).…”

Novel germline mutations in BRCA2 gene among 96 hereditary breast and breast–ovarian cancer families from Kerala, South India

“…However, none of the four male breast cancer patients included in our study showed BRCA2 mutation (except an intronic alteration in family MBF88, Table 3). Few other investigators also failed to demonstrate such association (Hamann et al 2002). It is presumed that some other genes (other than BRCA2) may be involved in the pathogenesis of male breast cancer in these families.…”