A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes

Abstract

The BRCA2 gene on chromosome 13 has been shown to be associated with familial male and female breast cancer. Here we describe a study on BRCA2 in 21 Icelandic families, including 9 with male breast cancer. We have previously reported linkage to the BRCA2 region in an Icelandic male breast cancer family and subsequently found a strong indication of linkage to BRCA2 and the same BRCA2 haplotype in breast cancer cases from 15 additional families, indicating a common origin. We describe a five base-pair deletion in exon 9 of BRCA2 in an affected male from the male breast cancer family. The same mutation occurs in all the families with the shared BRCA2 haplotype indicating a founder effect. Among mutation carriers there are 12 males with breast cancer, which accounts for 40% of all males diagnosed with breast cancer in Iceland over the past 40 years. Three of them have no family history of breast cancer indicating that this mutation may have variable penetrance. The same BRCA2 mutation appears to be associated with different cancer phenotypes in this population including male and female breast cancer, prostate cancer, pancreas cancer and ovarian cancer.

Cancer incidence in the Falkland Islands

“…The highly significant excess of male breast cancers (based on two cases) raises the possibility of a genetic basis, as male breast cancer has been found associated with the BRCA2 gene (Thorlacius et al, 1996;Friedman et al, 1997). The cases, however, were not from families in which breast cancer or ovarian cancer are known to have occurred in women; they were not known to have any ancestors in common, and had not been tested for BRCA2.…”

Somatic mutations in the BRCA2 gene and high frequency of allelic loss of BRCA2 in sporadic male breast cancer

“…1 Unlike BRCA1 mutations, germline mutations of BRCA2 are involved in the development of a considerable number of male breast cancer. [2][3][4][5] LOH on chromosome 13q12-13 was reported in 20-60% of sporadic breast tumors. 6 -8 Such high frequency of allelic loss at BRCA2 locus points to an important role of this gene in the development and progression of sporadic breast cancer.…”

“…12 BRCA2 mutations were detected in individuals with different tumor types, including male and female breast cancer and cancer of the prostate, pancreas, ovary, colon, stomach, thyroid, cervix and endometrium. 3,13 Tumors from BRCA2 mutation carriers usually show loss of heterozygosity on chromosome 13q12-13 and the losses always involve the wild-type chromosome. 13,14 Similarly, in our study all tumors of BRCA2 carriers showed LOH at BRCA2 locus.…”

“…However, most studies were conducted to evaluate the frequency of germline BRCA2 mutations in male breast cancer patients. 2,5,23,24 Only Thorlacius et al 3 and Haraldsson et al 4 screened tumor tissues for BRCA2 mutations, nevertheless only germline mutations were detected. On the contrary, we identified 5 somatic BRCA2 mutations in a set of 23 sporadic male breast cancers.…”

The BRCA2 is a histone acetyltransferase

“…Interestingly, BRCA2 was found to be more associated with male breast cancer compared to BRCA1 (Wooster et al, 1994). Patients with BRCA2 mutations were also found to be at a higher risk with a variety of other cancers including carcinomas of pancreas, prostate and colon (Thorlacius et al, 1996;Phelan et al, 1996;Gudmundsson et al, 1995;Tonin et al, 1995). The BRCA2 gene is composed of 27 exons and encodes a protein of 3418 amino-acids with no signi®cant homology to any known protein Bork et al, 1996).…”