<b>
                     <i>BRCA</i>
                  </b> Mutations and Risk of Prostate Cancer in Ashkenazi Jews

Kirchhoff, Tomas; Kauff, Noah D.; Mitra, Nandita; Nafa, Kedoudja; Huang, Helen J.; Palmer, Crystal; Gulati, T; Wadsworth, E.; Donat, S. Machele; Robson, Mark E.; Ellis, Nathan A.; Offit, Kenneth

doi:10.1158/1078-0432.ccr-03-0604

Cited by 148 publications

(115 citation statements)

References 25 publications

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“…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.…”

Section: Discussionmentioning

confidence: 97%

The role of BRCA1 and BRCA2 in prostate cancer

Castro¹,

Eeles²

2012

Asian J Androl

131

105

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One of the strongest risk factors for prostate cancer is a family history of the disease. Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men f65 years). Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes. The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease. As we present here, BRCA germline mutations, mainly in the BRCA2 gene, are one of those predictive factors. We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sporadic cases with similar characteristics.

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Section: Discussionmentioning

confidence: 97%

The role of BRCA1 and BRCA2 in prostate cancer

Castro¹,

Eeles²

2012

Asian J Androl

131

105

View full text Add to dashboard Cite

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“…Given that only one-half of the first-degree relatives are expected to be gene carriers, this corresponds to a relative risk of prostate cancer, given a BRCA2 mutation, of approximately five. Kirchoff et al (2004) tested 251 unselected Ashkenazi Jewish men with prostate cancer from the New York area for the two founder mutations in BRCA1 and the one in BRCA2. They also tested 1472 Ashkenazi controls.…”

Section: Discussionmentioning

confidence: 99%

Rapid progression of prostate cancer in men with a BRCA2 mutation

et al. 2008

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Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (Po0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation. British Journal of Cancer (2008) BRCA2 is a multisite cancer gene. It is generally thought that BRCA2 mutations primarily affect women, but men with mutations are also at elevated cancer risk. The two most important cancer sites for males who carry a mutation are the prostate and the pancreas (Liede et al, 2004). The risk of prostate cancer is elevated approximately fivefold in BRCA2 carriers, compared to noncarriers. Genetic counselors and urologists advise men with BRCA2 mutations to undergo surveillance with annual PSA testing from the age of 40 years -a recommendation based on the perceived effectiveness of prostate screening. It is hoped that screening leads to early diagnosis, when cure rates are high. A recent study from Iceland suggests that prostate cancers in men with a BRCA2 mutation may be unusually aggressive (Tryggvadottir et al, 2007). Tryggvadottir et al (2007) identified the Icelandic founder mutation (BRCA2 999 del5) in 30 of the 527 prostate cancer patients studied (5.7%). Men with a BRCA2 mutation had a median survival of only 2.1 years, compared with 12.4 years for noncarriers (Po0.01). The survival difference could not be explained by stage or grade. It is important that these findings be replicated because of the implications for the screening of men with a BRCA2 mutation. We identified the prostate cancer patients in a panel of 2673 families with a BRCA1 or a BRCA2 mutation and estimated survival of the men in the two subgroups. METHODSMen with prostate cancer were included in the survival analysis if they were from a family with a BRCA mutation and if they were (a) known to carry the familial BRCA mutation, or (b) if they were a first-degree relative of a known carrier, or (c) if they were a firstdegree relative of a woman diagnosed with breast or ovarian cancer. For each eligible man with prostate cancer, information was collected on age at diagnosis, age at death (if deceased) or age when last known alive (if alive). Information was collected by the

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“…However, we estimate that o1% of early-onset prostate cancers in the general US Caucasian population can be attributed to these rare disease-associated BRCA2 mutations. British Journal of Cancer (2007) (BCLC, 1999;Johannsson et al, 1999;Eerola et al, 2001;Tulinius et al, 2002;Bermejo and Hemminki, 2004;van Asperen et al, 2005), kin-cohort studies of cancer incidence among relatives of population-based breast or ovarian cancer cases (Loman et al, 2003;Risch et al, 2006), as well as studies of populations who harbour founder BRCA2 mutations (Sigurdsson et al, 1997;Struewing et al, 1997, Kirchhoff et al, 2004 suggest that men who carry a diseaseassociated BRCA2 allele have an increased relative risk (RR) of prostate cancer (two-to five-fold elevation). Two of the family studies in which data were stratified on age at diagnosis of prostate cancer reported that the RR was even higher (seven-to eight-fold increase) in men diagnosed before age 65 years (BCLC, 1999;van Asperen et al, 2005).…”

mentioning

confidence: 99%

Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer

et al. 2007

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Studies of families who segregate BRCA2 mutations have found that men who carry disease-associated mutations have an increased risk of prostate cancer, particularly early-onset disease. A study of sporadic prostate cancer in the UK reported a prevalence of 2.3% for protein-truncating BRCA2 mutations among patients diagnosed at ages p55 years, highlighting the potential importance of this gene in prostate cancer susceptibility. To examine the role of protein-truncating BRCA2 mutations in relation to early-onset prostate cancer in a US population, 290 population-based patients from King County, Washington, diagnosed at ages o55 years were screened for germline BRCA2 mutations. The coding regions, intron -exon boundaries, and potential regulatory elements of the BRCA2 gene were sequenced. Two distinct protein-truncating BRCA2 mutations were identified in exon 11 in two patients. Both cases were Caucasian, yielding a mutation prevalence of 0.78% (95% confidence interval (95%CI) 0.09 -2.81%) and a relative risk (RR) of 7.8 (95%CI 1.8 -9.4) for early-onset prostate cancer in white men carrying a protein-truncating BRCA2 mutation. Results suggest that protein-truncating BRCA2 mutations confer an elevated RR of early-onset prostate cancer. However, we estimate that o1% of early-onset prostate cancers in the general US Caucasian population can be attributed to these rare disease-associated BRCA2 mutations. British Journal of Cancer (2007) (BCLC, 1999;Johannsson et al, 1999;Eerola et al, 2001;Tulinius et al, 2002;Bermejo and Hemminki, 2004;van Asperen et al, 2005), kin-cohort studies of cancer incidence among relatives of population-based breast or ovarian cancer cases (Loman et al, 2003;Risch et al, 2006), as well as studies of populations who harbour founder BRCA2 mutations (Sigurdsson et al, 1997;Struewing et al, 1997, Kirchhoff et al, 2004 suggest that men who carry a diseaseassociated BRCA2 allele have an increased relative risk (RR) of prostate cancer (two-to five-fold elevation). Two of the family studies in which data were stratified on age at diagnosis of prostate cancer reported that the RR was even higher (seven-to eight-fold increase) in men diagnosed before age 65 years (BCLC, 1999;van Asperen et al, 2005). These findings suggest that proteintruncating BRCA2 mutations may play a role in prostate cancer susceptibility. However, the majority of studies that have investigated the role of BRCA2 mutations in hereditary prostate cancer (HPC) families, which usually include men diagnosed with prostate cancer at younger ages, have reported no diseaseassociated mutations (Wilkens et al, 1999;Gayther et al, 2000;Sinclair et al, 2000;Agalliu et al, 2007).To date, only one study has assessed the contribution of BRCA2 mutations in early-onset sporadic prostate cancer (Edwards et al, 2003). In a case series of 263 men in the UK diagnosed with prostate cancer at younger ages (p55 years), and who were not selected on the basis of either breast or prostate cancer family history, the prevalence of protein-truncating BRCA2 mu...

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BRCA Mutations and Risk of Prostate Cancer in Ashkenazi Jews

Cited by 148 publications

References 25 publications

The role of BRCA1 and BRCA2 in prostate cancer

The role of BRCA1 and BRCA2 in prostate cancer

Rapid progression of prostate cancer in men with a BRCA2 mutation

Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer

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