The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel

Abstract

Inherited predisposition occurs in 5–10% of all prostate cancer (CaP) patients, but the genes involved in conferring genetic susceptibility remain largely unknown. Several lines of evidence indicate that germline mutations in BRCA1 and BRCA2 might be associated with an increased risk for CaP. Three mutations in these two genes (185delAG and 5382InsC ( BRCA1 ) and 6174delT ( BRCA2 ) occur in about 2.5% of the general Ashkenazi population, and the 185delAG BRCA1 mutation, in up to 1% of non-Ashkenazi Jews. In order to assess the contribution of these germline mutations to prostate cancer in Jewish Israeli patients, we tested 174 unselected prostate cancer patients (95 of Ashkenazi origin) for these mutations by PCR amplification and modified restriction enzyme digests. Patient’s age range was 45–81 years (median 66), and in 24 (14.4%) the disease was diagnosed prior to 55 years of age. Nineteen (11%) and 12 (6.9%) patients had a first or second degree relative with CaP or breast cancer, respectively. Overall, five mutation carriers were detected: 2/152 (1.3%) 185delAG, 2/104 (2%) 5382InsC, and 1/158 (0.6%) 6174delT. In all carriers, the disease was diagnosed after the age of 55, and only one of them had a family history of breast and CaP. In addition, no allelic losses at the BRCA1 locus were demonstrated in 17 patients with a family history of CaP, using seven microsatellite markers. We conclude that the rate of the predominant Jewish BRCA1 and BRCA2 mutations in CaP patients does not significantly differ from that of the general population, and that mutational inactivation of the BRCA1 is rare in familial CaP. Thus, germline BRCA1 and BRCA2 mutations probably contribute little to CaP occurrence, to inherited predisposition, and to early onset disease in Jewish individuals. © 2000 Cancer Research Campaign

The frequency of the predominant Jewish mutations in BRCA1 and BRCA2 in unselected Ashkenazi colorectal cancer patients

“…Of note, had we excluded patients with personal or familial history of BC from the patient cohort as well as from the control group analysed, the lack of association between these mutations and CRC would be even more striking. Taken together with the recent publications showing these specific mutations do not increase the risk for prostate cancer in this ethnic group (Lehrer et al, 1998;Hubert et al, 1999;Vazina et al, 2000), we can conclude that the predominant Ashkenazi Jewish BRCA1 and BRCA2 mutations do not contribute to the pathogenesis of CRC. Thus, it seems that the two major indications for performing BRCA1/2 genetic testing in men are the personal risk for developing BC (Struewing et al, 1999) and the risk of transmitting the mutated alleles to their daughters.…”

Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype

“…It demonstrated that BRCA2 mutation carriers have a relative risk (RR) of PRCA of 4.65 rising to 7.33 below the age of 65 years and BRCA1 mutation carriers have an RR of PRCA of 1.82 under the age of 65 years (BCLC, 1999; Thompson et al, 2002). Similar data have been recorded in the AJ population (Struewing et al, 1997;Warner et al, 1999;Giusti et al, 2003), although smaller clinical studies have generally not demonstrated an increased frequency of founder BRCA1/2 mutations among Jewish men with PRCA (Lehrer et al, 1998;Hubert et al, 1999;Nastiuk et al, 1999;Vazina et al, 2000). In the current data set, six men were identified from a previous study conducted at The Institute of Cancer Research, as described in the Materials and Methods section.…”

The role of BRCA1 and BRCA2 in prostate cancer

“…It has been estimated that ,2% of this population carries at least one of these mutations. [77][78][79][80] Even in this population, the results of these epidemiological studies have been contradictory, but many of them were underpowered, due to small sample size or lack of covariate information. 22,[81][82][83][84][85][86] Another BRCA2 founder mutation that has been extensively studied is the Icelandic BRCA2 999del5 mutation.…”