BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients

Kóte-Jarai, Zsofia; Leongamornlert, Daniel; Saunders, Ed; Tymrakiewicz, Malgorzata; Castro, Elena; Mahmud, Nadiya; Guy, Michelle; Edwards, Sandra E.; O'Brien, Lynne T.; Sawyer, Elinor J.; Hall, Amanda L.; Wilkinson, Rosemary; Dadaev, Tokhir; Goh, Chee; Easton, Douglas F.; Goldgar, David E.; Eeles, Rosalind

doi:10.1038/bjc.2011.383

Cited by 344 publications

(283 citation statements)

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“…Johannesdottir et al 87 reported that this mutation was present in 2.7% of unselected Icelandic patients diagnosed with PCa at age f65 years. This prevalence is double the prevalence of germline BRCA2 mutations reported by Kote-Jarai et al 23 and Agalliu et al 22 in two cohorts of PCa patients diagnosed at age f65 years (1.2% and 0.78%, respectively). In these latter two studies, patients were screened for any 22 mutation, not only the founder ones.…”

Section: Discussionmentioning

confidence: 60%

“…23,24,51,[68][69][70][71][72][73] However, one of the challenges of studies analysing the susceptibility of PCa in BRCA mutation carriers is the low incidence of germline mutations in those genes in the general population which is estimated to be between 0.07% and 0.24% in different studies, 72,[74][75][76] and therefore, results have often been inconsistent. The ethnic population that has more extensively been studied is the Ashkenazim Jewish, due to the relative high incidence of three founder mutations (BRCA1 185delA, BRCA1 5382insC and BRCA2 6174delT).…”

Section: Discussionmentioning

confidence: 99%

“…7 Genome-wide association studies (GWAs) have identified 46 susceptibility loci associated with PCa [8][9][10][11][12][13][14][15][16][17][18][19][20] that individually contribute to a small increase in PCa risk, but which taken together, could explain more than 25% of the excess of PCa familial risk. 13 Although present in only 1%-2% of sporadic PCa cases [21][22][23] germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of PCa (8.6-fold in men f65 years). 23 BRCA1 has also been associated with an increased risk of sporadic PCa (3.5-fold), even though germline mutations in this gene have only been observed in 0.44% of PCa cases (Leongamonlert et al, in press).…”

Section: Introductionmentioning

confidence: 99%

“…13 Although present in only 1%-2% of sporadic PCa cases [21][22][23] germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of PCa (8.6-fold in men f65 years). 23 BRCA1 has also been associated with an increased risk of sporadic PCa (3.5-fold), even though germline mutations in this gene have only been observed in 0.44% of PCa cases (Leongamonlert et al, in press). Lifetime risk of PCa in BRCA2 mutation carriers has been estimated to be 20%, 24 while for BRCA1, the risk is 9.5% by age 65 years (Leongamonlert et al, in press), similar to that in non-carriers.…”

Section: Introductionmentioning

confidence: 99%

“…24 We have recently concluded two large studies reporting an 3.5-fold and 8.6-fold increase in the risk of PCa for BRCA1 and BRCA2 mutation carriers by age 65, respectively (Leongmonrlert et al, in press). 23 BRCA1 and BRCA2 are tumour suppressor genes and both are inherited in an autosomal dominant fashion with incomplete penetrance. Tumorigenesis in individuals with germline mutations in the BRCA genes requires somatic inactivation of the remaining wild-type allele.…”

Section: Introductionmentioning

confidence: 99%

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The role of BRCA1 and BRCA2 in prostate cancer

Castro¹,

Eeles²

2012

Asian J Androl

135

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: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The role of BRCA1 and BRCA2 in prostate cancer

Castro¹,

Eeles²

2012

Asian J Androl

135

105

View full text Add to dashboard Cite

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Characterization of the Cancer Spectrum in Men With GermlineBRCA1andBRCA2Pathogenic Variants

Silvestri¹,

Leslie²,

Barnes³

et al. 2020

JAMA Oncol

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and the CIMBA Group IMPORTANCE The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. OBJECTIVE To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.MAIN OUTCOMES AND MEASURES BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.RESULTS Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.CONCLUSIONS AND RELEVANCE Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

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Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer

Darst,

Saunders,

Dadaev

et al. 2023

JAMA Oncol

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ImportanceGermline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease.ObjectiveTo identify genes associated with aggressive PCa.Design, Setting, and ParticipantsA 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa.ExposureSequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels.Main Outcomes and MeasuresThe primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa.ResultsA total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10−6), followed by NBN (P = 1.7 × 10−4). This study found nominal evidence (P &lt; .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa.Conclusions and RelevanceThe findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.

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BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients

Cited by 344 publications

References 25 publications

The role of BRCA1 and BRCA2 in prostate cancer

The role of BRCA1 and BRCA2 in prostate cancer

Characterization of the Cancer Spectrum in Men With GermlineBRCA1andBRCA2Pathogenic Variants

Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer

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