Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis
by
,
Anna Amela Valsecchi
1, 
Rossana Dionisio
1,
Olimpia Panepinto
1,
Jessica Paparo
1,
Andrea Palicelli
2
,
Francesca Vignani
1 and
Massimo Di Maio
1,*
1
Department of Oncology, University of Turin, Ordine Mauriziano Hospital, 10128 Turin, Italy
2
Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(9), 2435; https://doi.org/10.3390/cancers15092435
Submission received: 20 February 2023
/
Revised: 5 April 2023
/
Accepted: 22 April 2023
/
Published: 24 April 2023
(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)
Abstract
:Simple Summary
Our updated systematic review and meta-analysis investigates the frequency of germline and somatic BRCA1 and BRCA2 mutations in patients with prostate cancer (PC), with subgroup analysis according to the type of mutation (germline or somatic mutations; mutation of BRCA1 and/or BRCA2) and according to the disease setting (any stage PC or metastatic PC or metastatic castration-resistant PC). As known, BRCA testing has recently become standard in clinical practice in prostate cancer because of new available target therapies. However, several open questions remain, in terms of the best time to perform it, the genes to look for (BRCA only or genes related to the DNA repair pathway of homologous recombination as well), and the optimal molecular analysis technique (somatic and/or germline testing or, in the future, liquid biopsy, which interestingly could assess both somatic and germline mutations simultaneously).
Abstract
In prostate cancer (PC), the presence of BRCA somatic and/or germline mutation provides prognostic and predictive information. Meta-analysis aims to estimate the frequency of BRCA mutations in patients with PC (PCp). In November 2022, we reviewed literature searching for all articles testing the proportion of BRCA mutations in PCp, without explicit enrichment for familiar risk. The frequency of germline and somatic BRCA1 and/or BRCA2 mutations was described in three stage disease populations (any/metastatic/metastatic castration-resistant PC, mCRPC). Out of 2253 identified articles, 40 were eligible. Here, 0.73% and 1.20% of any stage PCp, 0.94% and 1.10% of metastatic PCp, and 1.21% and 1.10% of mCRPC patients carried germline and somatic BRCA1 mutation, respectively; 3.25% and 6.29% of any stage PCp, 4.51% and 10.26% of metastatic PCp, and 3.90% and 10.52% of mCRPC patients carried germline and somatic BRCA2 mutation, respectively; and 4.47% and 7.18% of any stage PCp, 5.84% and 10.94% of metastatic PCp, and 5.26% and 11.26% of mCRPC patients carried germline and somatic BRCA1/2 mutation, respectively. Somatic mutations are more common than germline and BRCA2 are more common than BRCA1 mutations; the frequency of mutations is higher in the metastatic setting. Despite that BRCA testing in PC is now standard in clinical practice, several open questions remain.
1. Introduction
In oncology, the demand for breast cancer gene (BRCA) genetic testing in various tumor types, such as ovarian, breast, pancreatic, and prostate cancer (PC), is rapidly and continuously increasing to predict the efficacy of cancer treatment, help physicians make decisions about therapeutic options, and assess individual and familial risk [1,2].
Regarding patients with PC, knowledge of the presence of BRCA1/2 mutations in cancer tissue (somatic mutations) or in peripheral blood (germline mutations) provides useful information of prognostic and predictive value.
In particular, first, BRCA mutation identification allows the planning of an appropriate therapeutic algorithm. Indeed, BRCA testing is essential to determine whether patients are eligible for new targeted and effective therapeutic strategies, such as poly-ADP-ribose polymerase inhibitors (PARPis). While treatment of metastatic PC has historically consisted of hormonal therapy with androgen deprivation, chemotherapy, and various radiotherapy approaches, the recent approval of PARPis, such as rucaparib and olaparib, has revolutionized the therapeutic algorithm of metastatic castration-resistant PC (mCRPC) and led to a marked improvement in clinical outcomes for patients with BRCA1/2 mutations [3,4,5,6,7].
Second, the identification of a pathogenetic germline variant in BRCA genes provides access to prevention programs, oncogenetic counseling of family members to identify high-risk carriers, special screening programs for early detection of BRCA-related heredo-familial tumors, and risk-reduction strategies [8].
BRCA testing requires standardized and harmonized procedures for germline and tumor DNA sequencing and for the interpretation of results; BRCA mutational status should be verified by a specialized laboratory using a validated analytical method [9,10].
According to the latest position paper of Italian Scientific Societies and the most recent European Society of Medical Oncology (ESMO) clinical practice guidelines, it is preferable to investigate pathogenetic BRCA variants in tumor tissue first, as the probability of detecting BRCA mutations is higher than with germline analysis. Patients who are found to have somatic pathogenic BRCA mutations should be referred for germline testing to identify possible constitutional and hereditary variants. Somatic testing should also be proposed to patients who initially underwent germline testing that did not identify a pathogenic variant and who are potential candidates for treatment with PARPis [9,10].
Data on the exact proportion of PC patients with BRCA mutations come from a 2018 systematic review and meta-analysis by Mok et al. They showed that the frequency of BRCA1 and BRCA2 carriers in PC patients was 0.9% and 2.2%, respectively [11].
As these data did not include more recent studies, and BRCA testing is now standard in clinical practice in metastatic PC thanks to the approval of specific treatments, we decided to conduct an updated systematic literature review and meta-analysis with the aim of evaluating the proportion of PC patients with BRCA mutations, dividing the data obtained into subgroups according to the type of mutation (germline or somatic mutations; mutation of BRCA1 and/or BRCA2) and according to the disease setting (any stage or metastatic PC or mCRPC).
2. Materials and Methods
This systematic review was conducted according to the Preferred Reporting Items for Systematic Review and meta-analysis (PRISMA) guidelines, as reported in Figure 1.
2.1. Search Strategy
An extensive literature search in PubMed, Web of Sciences, and Scopus databases was performed in November 2022 to identify all articles testing the proportion of BRCA1 and BRCA2 mutations in patients with PC.
The following keywords were used in our search strategy: “(prostate cancer) and (BRCA)”, “(prostate cancer) and (BRCA1 gene)”, “(prostate cancer) and (BRCA2 gene)”, “(prostate cancer) and (BRCA mutation)”, “(prostate cancer) and (BRCA testing)”, “(prostate cancer) and (germline BRCA)”, and “(prostate cancer) and (somatic BRCA)”. References of the identified articles were also checked manually to identify additional eligible items.
Initial screening was performed by one investigator (A.A.V.) and ineligible results were identified based on the titles and abstracts. If the study’s topic could not be ascertained from its title or abstract, the full-text version would be retrieved for evaluation. Disagreement was resolved by discussion or consensus with another co-author (M.D.M.).
2.2. Study Selection
To have sufficient data to calculate the number of BRCA mutation carriers among patients with PC, studies were screened for eligibility using the following inclusion criteria: (1) participants must be patients with PC, regardless of disease stage; (2) included studies must report the proportion of patients with BRCA mutations tested by somatic and/or germline testing, regardless of the gene involved (BRCA1 or BRCA2 or any BRCA) and mutation variant; and (3) articles must be in English and published between 2000 and 2022.
The following criteria were used as exclusion criteria: (1) participants with established risk factors for PC such as patients with inherited PC or patients with relatives with PC and (2) case reports and reviews.
2.3. Data Collection
For each eligible article, the following data were collected: (1) first author’s name; (2) year of publication; (3) total number of patients; (4) number of patients with or without BRCA mutations; (5) details of population disease setting: any stage PC, metastatic PC, and mCRPC; and (6) details of type of BRCA mutation: germline, somatic, BRCA1, and BRCA2.
2.4. Statistical Methods
The meta-analysis of the proportion of patients with PC with BRCA mutations was performed with MedCalc Statistical Software version 20.211 (MedCalc Software Ltd., Ostend, Belgium; https://www.medcalc.org; 2023). The software uses a Freeman–Tukey transformation (arcsine square root transformation) to calculate the weighted summary proportion under the fixed and random effects model. Heterogeneity is measured by Cochran’s Q, calculated as the weighted sum of squared differences between the individual study proportion and the pooled proportion across studies. Q is distributed as a chi-square statistic with k (number of studies) minus 1 degrees of freedom. The I2 statistic describes the percentage of variation across studies that is due to heterogeneity rather than chance. I2 = 100% × (Q − df)/Q.
2.5. Role of Funding Source
There was no funding source for this systematic review and meta-analysis. All authors had full access to all data and the corresponding author (M.D.M.) had the final responsibility for the decision to submit for publication.
3. Results
Our research items led to the identification of 2253 titles. After removing duplicates, non-pertinent items and ineligible studies, 40 articles were included in this systematic review and meta-analysis (Figure 1; Table 1) [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51].
See Appendix A for all detailed statistical results of the meta-analysis.
3.1. Meta-Analysis: Proportion of Patients with Prostate Cancer with BRCA1 Mutation
3.1.1. Proportion of Patients with Any Stage PC with BRCA1 Mutation
The proportion of germline BRCA1 mutation carriers among patients with any stage PC was available from 31 articles, for a total of 32,525 patients, and was equal to 0.73% (95% confidence interval, CI: 0.51–1.00), with significant heterogeneity (I2 = 81.19%; p < 0.0001) (Figure 2a).
The proportion of somatic BRCA1 mutation carriers among patients with any stage PC was available from 10 articles, for a total of 3229 patients, and was equal to 1.20% (95% CI: 0.85–1.60), without significant heterogeneity (I2 = 0.00%; p = 0.7423) (Figure 2b).
3.1.2. Proportion of Patients with Metastatic PC with BRCA1 Mutation
The proportion of germline BRCA1 mutation carriers among patients with metastatic PC was available from 10 articles, for a total of 3963 patients, and was equal to 0.94% (95% CI: 0.19–2.23), with significant heterogeneity (I2 = 88.85%; p < 0.0001) (Figure 2c).
The proportion of somatic BRCA1 mutation carriers among patients with metastatic PC was available from six articles, for a total of 1384 patients, and was equal to 1.10% (95% CI: 0.62–1.71), without significant heterogeneity (I2 = 0.00%; p = 0.9224) (Figure 2d).
3.1.3. Proportion of Patients with mCRPC with BRCA1 Mutation
The proportion of germline BRCA1 mutation carriers among patients with mCRPC was available from seven articles, for a total of 2571 patients, and was equal to 1.21% (95% CI: 0.053–3.84), with significant heterogeneity (I2 = 92.36%; p < 0.0001) (Figure 2e).
The proportion of somatic BRCA1 mutation carriers among patients with mCRPC was available from five articles, for a total of 1243 patients, and was equal to 1.10% (95% CI: 0.60–1.76), without significant heterogeneity (I2 = 0.00%; p = 0.8425) (Figure 2f).
3.2. Meta-Analysis: Proportion of Patients with Prostate Cancer with BRCA2 Mutation
3.2.1. Proportion of Patients with Any Stage PC with BRCA2 Mutation
The proportion of germline BRCA2 mutation carriers among patients with any stage PC was available from 30 articles, for a total of 29,813 patients, and was equal to 3.25% (95% CI: 2.54–4.04), with significant heterogeneity (I2 = 90.96%; p < 0.0001) (Figure 3a).
The proportion of somatic BRCA2 mutation carriers among patients with any stage PC was available from 10 articles, for a total of 3229 patients, and was equal to 6.29% (95% CI: 3.79–9.38), with significant heterogeneity (I2 = 89.14%; p < 0.0001) (Figure 3b).
3.2.2. Proportion of Patients with Metastatic PC with BRCA2 Mutation
The proportion of germline BRCA2 mutation carriers among patients with metastatic PC was available from 10 articles, for a total of 3963 patients, and was equal to 4.51% (95% CI: 2.93–6.42), with significant heterogeneity (I2 = 81.54%; p < 0.0001) (Figure 3c).
The proportion of somatic BRCA2 mutation carriers among patients with metastatic PC was available from six articles, for a total of 1384 patients, and was equal to 10.26% (95% CI: 7.92–12.85), without significant heterogeneity (I2 = 38.42%; p = 0.1498) (Figure 3d).
3.2.3. Proportion of Patients with mCRPC with BRCA2 Mutation
The proportion of germline BRCA2 mutation carriers among patients with mCRPC was available from seven articles, for a total of 2571 patients, and was equal to 3.90% (95% CI: 2.13–6.16), with significant heterogeneity (I2 = 76.71%; p = 0.0002) (Figure 3e).
The proportion of somatic BRCA2 mutation carriers among patients with mCRPC was available from five articles, for a total of 1243 patients, and was equal to 10.52% (95% CI: 7.64–13.81), without significant heterogeneity (I2 = 49.50%; p = 0.0945) (Figure 3f).
3.3. Meta-Analysis: Proportion of Patients with Prostate Cancer with Any BRCA Mutation
3.3.1. Proportion of Patients with Any Stage PC with Any BRCA Mutation
The proportion of germline BRCA1/2 mutation carriers among patients with any stage PC was available from 29 articles, for a total of 33,784 patients, and was equal to 4.47% (95% CI: 3.38–5.70), with significant heterogeneity (I2 = 95.57%; p < 0.0001) (Figure 4a).
The proportion of somatic BRCA1/2 mutation carriers among patients with any stage PC was available from 10 articles, for a total of 3229 patients, and was equal to 7.18% (95% CI: 4.89–9.87), with significant heterogeneity (I2 = 84.17%; p < 0.0001) (Figure 4b).
3.3.2. Proportion of Patients with Metastatic PC with Any BRCA Mutation
The proportion of germline BRCA1/2 mutation carriers among patients with metastatic PC was available from 11 articles, for a total of 11,670 patients, and was equal to 5.84% (95% CI: 3.72–8.41), with significant heterogeneity (I2 = 93.61%; p < 0.0001) (Figure 4c).
The proportion of somatic BRCA1/2 mutation carriers among patients with metastatic PC was available from six articles, for a total of 1384 patients, and was equal to 10.94% (95% CI: 8.73–13.36), without significant heterogeneity (I2 = 29.07%; p = 0.2170) (Figure 4d).
3.3.3. Proportion of Patients with mCRPC with Any BRCA Mutation
The proportion of germline BRCA1/2 mutation carriers among patients with mCRPC was available from seven articles, for a total of 2571 patients, and was equal to 5.26% (95% CI: 2.18–9.57), with significant heterogeneity (I2 = 91.57%; p < 0.0001) (Figure 4e).
The proportion of somatic BRCA1/2 mutation carriers among patients with mCRPC was available from five articles, for a total of 1243 patients, and was equal to 11.26% (95% CI: 8.49–14.38), without significant heterogeneity (I2 = 42.38%; p = 0.1390) (Figure 4f).
4. Discussion
In this systematic review and meta-analysis, we collected all papers describing the frequency of somatic and/or germline BRCA1 and BRCA2 mutations in patients with PC. We analyzed this frequency in three populations of patients: all PC patients regardless of the stage, patients with metastatic PC, and patients with mCRPC.
First, although the complete information about somatic and germline status was available only in a subset of studies, we confirmed that, overall, somatic BRCA mutations are markedly more frequent than germline mutations: 7.18% versus 4.47%, respectively, in all patients with PC regardless of the stage of PC disease; 10.94% versus 5.84%, respectively, in patients with metastatic disease; and 11.26% versus 5.26%, respectively, in patients with mCRPC. Data obtained considering mutations of BRCA1 or BRCA2 separately confirmed a higher frequency of somatic mutations than germline mutations for both genes.
Second, both germline and somatic BRCA2 mutations are more common than BRCA1 mutations in both metastatic and patients with any stage PC. Specifically, among metastatic patients, 10.26% and 4.51% of cases have somatic and germline BRCA2 mutations, respectively, while 1.1% and 0.94% have somatic and germline BRCA1 mutations, respectively. Among patients with any stage PC, 6.29% and 3.25% have somatic and germline BRCA2 mutations, respectively, while 1.20% and 0.73% have somatic and germline BRCA1 mutations, respectively.
Finally, the frequency of BRCA mutations is higher in the series including only patients with metastatic disease than in the whole population of all patients studied, regardless of stage. Namely, the frequency of somatic BRCA1/2 mutations is 10.94% in patients with metastatic disease (11.26% when the analysis is limited to the castration-resistant setting) and 7.18% in all patients with any stage PC.
Similar to other solid tumors, including breast and ovarian cancer, in prostate cancer, the presence of BRCA mutation is an important clinical factor with prognostic and predictive value, especially owing to the recent introduction of target therapies such as PARPis into clinical practice. To date, these drugs have only been approved for mCRPC disease, although several studies are underway to predict their use in earlier stages of PC [52,53,54]. Therefore, molecular characterization of patients with PC is essential to avoid depriving them of a potential effective therapeutic option.
Our data confirm that many more cases can be identified with the somatic test than with the germline test alone. Therefore, the possibility of performing the somatic test must be guaranteed in all oncological centers. Until a few years ago, the only relevant determination in clinical practice was the search for germline mutations, in the context of genetic counseling for known or suspected hereditary cases. Nowadays, with the availability of target drugs, the determination of BRCA mutational status becomes relevant for therapeutic choices, and this implies a marked increase in the number of cases eligible for testing, as well as the need to obtain results more quickly in order to allow timely therapeutic decisions. This is a good example of the risk of disparities among different countries and different centers, owing to the asymmetry in reimbursement systems and in technical pathways for carrying out molecular tests; that is, patients could be at risk of unequal access not only to drugs, but also to tests.
In our meta-analysis, we focused on evaluating only the rate of BRCA1 and BRCA2 genes. Actually, although the real predictive value of other genes is controversial, mutations in genes related to the DNA repair pathway of homologous recombination (HR) (HRD-positive patients) have also been proposed and studied as predictive factors for PARPis. Therefore, in addition to BRCA mutations, other HRD-related gene aberrations may also serve as novel biomarkers for predicting the efficacy of PARPis [55].
However, in PC, the recommendations in the various international guidelines are not entirely congruent.
The 2022 Italian Association of Medical Oncology (AIOM) guidelines recommend BRCA testing for all patients with metastatic PC, without a recommendation about other genes. Namely, the indication to perform the test is also extended to patients who meet certain criteria regarding personal and family history, number of affected relatives, cancer type, multiple primary tumors, and age at diagnosis, as well as histologic, immunohistochemical, and molecular tumor characteristics [9].
Instead, European guidelines, issued by ESMO in 2020, recommend that tissue-based molecular assays may be used in conjunction with clinicopathological factors for treatment decisions in localized prostate cancer; germline testing for BRCA2 and other DDR genes associated with cancer predisposition syndromes is recommended in patients with a family history of cancer and should be considered in all patients with metastatic PC; tumor testing for HR genes can be considered in patients with mCRPC [10].
Still somewhat different are the recommendations of the National Comprehensive Cancer Network (NCCN) guidelines published in 2023: germline multigene testing that includes at least BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, and PMS2 is recommended if the patient is affected by metastatic, regional (node positive), very-high-risk localized, or high-risk localized PC (diagnosed at any age) and/or if certain criteria about family history and/or ancestry are met, while tumor testing for alterations in HR DNA repair genes, such as BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, and CDK12, is recommended in patients with metastatic PC and can be considered in patients with regional PC [5].
The test has also recently acquired, in addition to the traditional implications for the management of hereditary–familial cases, implications for the therapeutic management of patients. At least in part, probably, this fact explains the heterogeneity between different recommendations and guidelines.
Our meta-analysis, although based on a systematic and updated review of the literature, has some important limitations.
First of all, the absence of individual patient data implies that the information on the characteristics of the patients in the studies is limited. Because the incidence of mutations according to individual characteristics for all patients, their ethnicity, or geographic origin are not uniformly available, clinical characteristics associated with the presence of a mutation could not be analyzed. As for the association with clinical stage, the higher frequency of mutations in patients with metastatic disease seems more relevant for somatic than for germline mutations. However, we are unable to establish the exact timing of the appearance of somatic mutations with respect to disease progression, also because most somatic tests are performed on tissue previously archived at the time of initial diagnosis. Only serial tests on tissue samples taken at different stages of the disease could establish whether, in cases of wildtype for germline mutations, the appearance of somatic mutations is an early event potentially associated with higher risk of metastases and a worse prognosis or simply a late event in the natural history of the disease. However, the execution of molecular testing on archived tissue is consistent with daily clinical practice. Thus, the collected data help to estimate the number of patients with PC with BRCA mutations that we can expect to see in clinical practice. In this scenario, it would be important for urologists to be aware at the time of a prostate biopsy that the tissue is not only needed for histologic analysis, but could also be useful for genetic analysis. The biopsy or tissue removed should be quantitatively sufficient for both analyses so that the patient is not biopsied again later.
Another limitation is the heterogeneity that characterizes the techniques of molecular analysis used in the studies included in the meta-analysis. Different techniques can be different for sensitivity and specificity, and this could contribute to the high heterogeneity found in the incidence of mutations among different studies. Furthermore, different BRCA mutations variants were not uniformly distinguished according to their predictive value.
Lastly, our meta-analysis did not include studies that investigated BRCA mutations using the liquid biopsy technique. According to recent studies, liquid biopsy seems to have a very interesting role for three main reasons.
First, a study by Tukachinsky et al. showed that there is a good agreement between data obtained from somatic testing and those obtained from liquid biopsy [46]. Thus, the liquid biopsy technique would allow to assess both somatic and germline mutations simultaneously using only one blood sample.
Second, a recent exploratory analysis of the PROfound study evaluated the efficacy of olaparib in patients with BRCA/ATM mutations investigated by liquid biopsy, showing that the clinical outcome endpoints were similar to those reached in the cohort in which mutations had been studied with somatic testing [3,56]. Therefore, this study highlights that the liquid biopsy technique could be a test with the same prognostic and predictive value as somatic testing.
Third, somatic testing has failure rates for several reasons, such as a lack of quantitatively sufficient tumor tissue or other technical difficulties. For example, in the PROfound study, the success rate of somatic testing was 69% [3]. In this scenario, liquid biopsy could exceed the limitations of somatic testing and become a valid and useful alternative.
Therefore, the role of liquid biopsy will become increasingly intriguing in the future because it could offer our patients with mCRPC a less invasive technique than somatic testing that can overcome its limitations while maintaining the ability to provide predictive and prognostic information.
5. Conclusions
In prostate cancer, knowledge of the presence of somatic and/or germline mutations of BRCA provides useful information of prognostic and predictive value to plan an appropriate therapeutic algorithm thanks to the introduction of new therapeutic options and ensure access to prevention programs and oncogenetic counseling.
In summary, as BRCA testing is now well-established in clinical practice, this meta-analysis aimed to describe the rate of BRCA mutations that clinicians should expect to see on a daily basis.
Meta-analysis demonstrates that somatic mutations are more common than germline mutations, BRCA2 mutations are more common than BRCA1 mutations in both metastatic patients and patients with any stage PC, and that the frequency of BRCA mutations is higher in the series including only patients with metastatic disease than in the whole population of all patients studied regardless of stage.
Because the test has recently acquired implications for the therapeutic management of patients with PC, the recommendations in the various international guidelines are not entirely congruent and, in this scenario, several questions remain for the future, both in terms of the best time to perform BRCA testing based on ongoing studies of the use of PARPis at an earlier stage of PC disease, as well as in terms of the genes to look for (BRCA or HRD panel) and the optimal molecular analysis technique (somatic and/or germline testing or liquid biopsy).
Author Contributions
Conceptualization, A.A.V. and M.D.M.; methodology, M.D.M.; software, M.D.M.; validation, R.D., A.P., F.V., O.P. and J.P.; formal analysis, M.D.M.; investigation, A.A.V.; data curation, A.A.V.; writing—original draft preparation, A.A.V.; writing—review and editing, M.D.M.; visualization, A.A.V.; supervision, R.D. and F.V. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding. For this study, A.P. was partially supported by the Italian Ministry of Health—Ricerca Corrente Annual Program 2023.
Data Availability Statement
The data presented in this study are available in Appendix A.
Conflicts of Interest
Massimo Di Maio received honoraria and had roles as consultant or advisor for AstraZeneca, Pfizer, Novartis, Roche, Takeda, Eisai, Merck Sharp & Dohme, Janssen, Astellas, Boehringer Ingelheim, Amgen, and Merck, outside this work; and received an institutional research grant by Tesaro—GlaxoSmithKline, outside this work. Other authors (A.A.V; R.D.; O.P.; J.P.; F.V.; A.P.) declare no conflict of interest.
Appendix A
This appendix has been provided by the authors to give readers additional information about their work.
Table A1.
Meta-analysis: proportion of unselected PC patients with somatic BRCA1 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Giusti, 2003 | 940 | 1.702 | 0.976 to 2.749 | 29.05 | 29.05 |
| Cancer Genome Atlas, 2015 | 333 | 1.201 | 0.328 to 3.047 | 10.31 | 10.31 |
| Robinson, 2015 | 150 | 0.667 | 0.0169 to 3.658 | 4.66 | 4.66 |
| Mateo, 2015 | 49 | 2.041 | 0.0517 to 10.854 | 1.54 | 1.54 |
| Sztupinszki, 2020 | 240 | 0.833 | 0.101 to 2.978 | 7.44 | 7.44 |
| Mota, 2020 | 64 | 0.000 | 0.000 to 5.601 | 2.01 | 2.01 |
| Tukachinsky, 2021 | 837 | 1.075 | 0.493 to 2.031 | 25.87 | 25.87 |
| Martinez Chanza, 2021 | 399 | 0.501 | 0.0608 to 1.799 | 12.35 | 12.35 |
| Jiang, 2021 | 74 | 0.000 | 0.000 to 4.863 | 2.32 | 2.32 |
| Uemura, 2022 | 143 | 0.699 | 0.0177 to 3.835 | 4.45 | 4.45 |
| Total (fixed effects) | 3229 | 1.199 | 0.853 to 1.637 | 100.00 | 100.00 |
| Total (random effects) | 3229 | 1.199 | 0.853 to 1.603 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 5.9758 |
| DF | 9 |
| Significance level | p = 0.7423 |
| I2 (inconsistency) | 0.00% |
| 95% CI for I2 | 0.00 to 43.62 |
Publication bias
| Egger’s test | |
| Intercept | −0.6710 |
| 95% CI | −1.9905 to 0.6484 |
| Significance level | p = 0.2746 |
| Begg’s test | |
| Kendall’s Tau | −0.2000 |
| Significance level | p = 0.4208 |
Table A2.
Meta-analysis: proportion of unselected PC patients with somatic BRCA2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Giusti, 2003 | 940 | 1.489 | 0.817 to 2.486 | 29.05 | 11.84 |
| Cancer Genome Atlas, 2015 | 333 | 3.303 | 1.660 to 5.834 | 10.31 | 11.11 |
| Robinson, 2015 | 150 | 12.000 | 7.269 to 18.301 | 4.66 | 9.95 |
| Mateo, 2015 | 49 | 14.286 | 5.942 to 27.242 | 1.54 | 7.18 |
| Sztupinszki, 2020 | 240 | 3.750 | 1.729 to 6.999 | 7.44 | 10.71 |
| Mota, 2020 | 64 | 9.375 | 3.519 to 19.297 | 2.01 | 7.94 |
| Tukachinsky, 2021 | 837 | 7.527 | 5.832 to 9.528 | 25.87 | 11.79 |
| Martinez Chanza, 2021 | 399 | 5.263 | 3.287 to 7.933 | 12.35 | 11.29 |
| Jiang, 2021 | 74 | 1.351 | 0.0342 to 7.301 | 2.32 | 8.34 |
| Uemura, 2022 | 143 | 12.587 | 7.634 to 19.162 | 4.45 | 9.86 |
| Total (fixed effects) | 3229 | 4.766 | 4.058 to 5.558 | 100.00 | 100.00 |
| Total (random effects) | 3229 | 6.294 | 3.792 to 9.375 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 82.8977 |
| DF | 9 |
| Significance level | p < 0.0001 |
| I2 (inconsistency) | 89.14% |
| 95% CI for I2 | 82.15 to 93.40 |
Publication bias
| Egger’s test | |
| Intercept | 3.0217 |
| 95% CI | −1.6936 to 7.7370 |
| Significance level | p = 0.1777 |
| Begg’s test | |
| Kendall’s Tau | 0.1556 |
| Significance level | p = 0.5312 |
Table A3.
Meta-analysis: proportion of unselected PC patients with somatic BRCA1/2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Giusti, 2003 | 940 | 3.191 | 2.163 to 4.525 | 29.05 | 12.62 |
| Cancer Genome Atlas, 2015 | 333 | 4.505 | 2.543 to 7.321 | 10.31 | 11.47 |
| Robinson, 2015 | 150 | 12.667 | 7.801 to 19.072 | 4.66 | 9.79 |
| Mateo, 2015 | 49 | 16.327 | 7.322 to 29.657 | 1.54 | 6.36 |
| Sztupinszki, 2020 | 240 | 4.583 | 2.310 to 8.053 | 7.44 | 10.88 |
| Mota, 2020 | 64 | 9.375 | 3.519 to 19.297 | 2.01 | 7.24 |
| Tukachinsky, 2021 | 837 | 8.602 | 6.791 to 10.710 | 25.87 | 12.53 |
| Martinez Chanza, 2021 | 399 | 5.764 | 3.689 to 8.524 | 12.35 | 11.74 |
| Jiang, 2021 | 74 | 1.351 | 0.0342 to 7.301 | 2.32 | 7.71 |
| Uemura, 2022 | 143 | 13.287 | 8.193 to 19.969 | 4.45 | 9.67 |
| Total (fixed effects) | 3229 | 6.072 | 5.274 to 6.950 | 100.00 | 100.00 |
| Total (random effects) | 3229 | 7.183 | 4.892 to 9.874 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 56.8386 |
| DF | 9 |
| Significance level | p < 0.0001 |
| I2 (inconsistency) | 84.17% |
| 95% CI for I2 | 72.49 to 90.89 |
Publication bias
| Egger’s test | |
| Intercept | 2.1709 |
| 95% CI | −1.8631 to 6.2049 |
| Significance level | p = 0.2498 |
| Begg’s test | |
| Kendall’s Tau | 0.1556 |
| Significance level | p = 0.5312 |
Table A4.
Meta-analysis: proportion of unselected PC patients with germline BRCA1 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Hamel, 2003 | 146 | 0.000 | 0.000 to 2.495 | 0.45 | 1.97 |
| Kirchhoff, 2004 | 251 | 1.992 | 0.650 to 4.587 | 0.77 | 2.64 |
| Cybulski, 2008 | 1793 | 0.446 | 0.193 to 0.877 | 5.51 | 4.45 |
| Agalliu, 2009 | 979 | 1.226 | 0.635 to 2.131 | 3.01 | 4.07 |
| Gallagher, 2010 | 832 | 0.721 | 0.265 to 1.563 | 2.56 | 3.94 |
| Fachal, 2011 | 905 | 0.110 | 0.00280 to 0.614 | 2.78 | 4.01 |
| Gallagher, 2012 | 88 | 3.409 | 0.709 to 9.641 | 0.27 | 1.41 |
| Cybulski, 2013 | 3750 | 0.373 | 0.204 to 0.626 | 11.52 | 4.72 |
| Robinson, 2015 | 150 | 0.667 | 0.0169 to 3.658 | 0.46 | 2.00 |
| Mateo, 2015 | 49 | 0.000 | 0.000 to 7.252 | 0.15 | 0.91 |
| Pritchard, 2016 | 692 | 0.867 | 0.319 to 1.878 | 2.13 | 3.78 |
| Na, 2017 | 799 | 0.501 | 0.137 to 1.277 | 2.46 | 3.90 |
| Antonarakis, 2018 | 172 | 0.581 | 0.0147 to 3.197 | 0.53 | 2.17 |
| Carneiro, 2018 | 1534 | 0.000 | 0.000 to 0.240 | 4.71 | 4.37 |
| Nicolosi, 2019 | 3607 | 1.192 | 0.864 to 1.602 | 11.08 | 4.71 |
| Wei, 2019 | 316 | 0.633 | 0.0767 to 2.267 | 0.97 | 2.92 |
| Castro, 2019 | 419 | 0.955 | 0.261 to 2.426 | 1.29 | 3.26 |
| Giri, 2019 | 1328 | 1.054 | 0.578 to 1.762 | 4.08 | 4.28 |
| Sonpavde, 2019 | 514 | 5.058 | 3.331 to 7.324 | 1.58 | 3.48 |
| Sztupinszki, 2020 | 240 | 0.833 | 0.101 to 2.978 | 0.74 | 2.58 |
| Pritzlaff, 2020 | 277 | 0.722 | 0.0876 to 2.584 | 0.85 | 2.76 |
| Mateo, 2020 | 175 | 1.714 | 0.355 to 4.928 | 0.54 | 2.19 |
| Momozawa, 2020 | 7636 | 0.183 | 0.100 to 0.307 | 23.46 | 4.87 |
| Mota, 2020 | 64 | 0.000 | 0.000 to 5.601 | 0.20 | 1.12 |
| Nguyen-Dumont, 2021 | 833 | 0.600 | 0.195 to 1.395 | 2.56 | 3.94 |
| Zhu, 2021 | 1836 | 0.381 | 0.153 to 0.784 | 5.64 | 4.46 |
| Truong, 2022 | 1883 | 0.584 | 0.292 to 1.043 | 5.79 | 4.47 |
| Kimura, 2022 | 549 | 0.364 | 0.0441 to 1.310 | 1.69 | 3.55 |
| Brady, 2022 | 437 | 0.458 | 0.0555 to 1.643 | 1.35 | 3.30 |
| So, 2022 | 120 | 0.000 | 0.000 to 3.027 | 0.37 | 1.75 |
| Lee, 2022 | 151 | 0.000 | 0.000 to 2.413 | 0.47 | 2.01 |
| Total (fixed effects) | 32,525 | 0.530 | 0.454 to 0.615 | 100.00 | 100.00 |
| Total (random effects) | 32,525 | 0.733 | 0.506 to 1.003 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 159.5048 |
| DF | 30 |
| Significance level | p < 0.0001 |
| I2 (inconsistency) | 81.19% |
| 95% CI for I2 | 74.05 to 86.37 |
Publication bias
| Egger’s test | |
| Intercept | 1.4944 |
| 95% CI | 0.03504 to 2.9537 |
| Significance level | p = 0.0451 |
| Begg’s test | |
| Kendall’s Tau | 0.09247 |
| Significance level | p = 0.4649 |
Table A5.
Meta-analysis: proportion of unselected PC patients with germline BRCA2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Hamel, 2003 | 146 | 1.370 | 0.166 to 4.861 | 0.49 | 2.62 |
| Kirchhoff, 2004 | 251 | 3.187 | 1.386 to 6.183 | 0.84 | 3.12 |
| Agalliu, 2009 | 979 | 1.839 | 1.093 to 2.890 | 3.28 | 3.89 |
| Gallagher, 2010 | 832 | 2.404 | 1.474 to 3.688 | 2.79 | 3.83 |
| Kote-Jarai, 2011 | 1832 | 1.037 | 0.626 to 1.615 | 6.14 | 4.05 |
| Gallagher, 2012 | 88 | 4.545 | 1.252 to 11.231 | 0.30 | 2.10 |
| Akbari, 2014 | 1904 | 1.366 | 0.894 to 1.994 | 6.38 | 4.06 |
| Robinson, 2015 | 150 | 6.000 | 2.780 to 11.084 | 0.51 | 2.65 |
| Mateo, 2015 | 49 | 6.122 | 1.281 to 16.866 | 0.17 | 1.50 |
| Pritchard, 2016 | 692 | 5.347 | 3.792 to 7.295 | 2.32 | 3.76 |
| Na, 2017 | 799 | 1.877 | 1.054 to 3.078 | 2.68 | 3.82 |
| Antonarakis, 2018 | 172 | 2.907 | 0.950 to 6.653 | 0.58 | 2.78 |
| Carneiro, 2018 | 1534 | 1.565 | 1.005 to 2.319 | 5.14 | 4.02 |
| Nicolosi, 2019 | 3607 | 4.547 | 3.890 to 5.278 | 12.09 | 4.15 |
| Wei, 2019 | 316 | 6.329 | 3.908 to 9.606 | 1.06 | 3.30 |
| Castro, 2019 | 419 | 3.341 | 1.839 to 5.543 | 1.41 | 3.49 |
| Giri, 2019 | 1328 | 4.518 | 3.465 to 5.778 | 4.45 | 3.98 |
| Sonpavde, 2019 | 514 | 5.058 | 3.331 to 7.324 | 1.73 | 3.61 |
| Sztupinszki, 2020 | 240 | 2.083 | 0.680 to 4.795 | 0.81 | 3.08 |
| Pritzlaff, 2020 | 277 | 3.971 | 1.999 to 6.994 | 0.93 | 3.20 |
| Mateo, 2020 | 175 | 8.000 | 4.443 to 13.058 | 0.59 | 2.80 |
| Momozawa, 2020 | 7636 | 1.087 | 0.867 to 1.346 | 25.59 | 4.20 |
| Mota, 2020 | 64 | 1.562 | 0.0396 to 8.401 | 0.22 | 1.77 |
| Nguyen-Dumont, 2021 | 833 | 2.281 | 1.379 to 3.539 | 2.79 | 3.83 |
| Zhu, 2021 | 1836 | 4.303 | 3.421 to 5.334 | 6.16 | 4.05 |
| Truong, 2022 | 1883 | 3.930 | 3.098 to 4.909 | 6.31 | 4.06 |
| Kimura, 2022 | 549 | 3.461 | 2.096 to 5.352 | 1.84 | 3.65 |
| Brady, 2022 | 437 | 0.686 | 0.142 to 1.993 | 1.47 | 3.52 |
| So, 2022 | 120 | 1.667 | 0.202 to 5.891 | 0.41 | 2.42 |
| Lee, 2022 | 151 | 9.934 | 5.667 to 15.855 | 0.51 | 2.66 |
| Total (fixed effects) | 29,813 | 2.473 | 2.300 to 2.656 | 100.00 | 100.00 |
| Total (random effects) | 29,813 | 3.246 | 2.539 to 4.037 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 320.7889 |
| DF | 29 |
| Significance level | p < 0.0001 |
| I2 (inconsistency) | 90.96% |
| 95% CI for I2 | 88.22 to 93.06 |
Publication bias
| Egger’s test | |
| Intercept | 2.4186 |
| 95% CI | 0.3057 to 4.5316 |
| Significance level | p = 0.0264 |
| Begg’s test | |
| Kendall’s Tau | 0.07126 |
| Significance level | p = 0.5802 |
Table A6.
Meta-analysis: proportion of unselected PC patients with germline BRCA1/2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Hamel, 2003 | 146 | 1.370 | 0.166 to 4.861 | 0.43 | 3.02 |
| Kirchhoff, 2004 | 251 | 5.179 | 2.786 to 8.694 | 0.75 | 3.37 |
| Agalliu, 2009 | 979 | 2.962 | 1.993 to 4.227 | 2.90 | 3.83 |
| Gallagher, 2010 | 832 | 3.125 | 2.051 to 4.545 | 2.46 | 3.80 |
| Gallagher, 2012 | 88 | 7.955 | 3.258 to 15.705 | 0.26 | 2.60 |
| Robinson, 2015 | 150 | 6.667 | 3.243 to 11.918 | 0.45 | 3.04 |
| Mateo, 2015 | 49 | 6.122 | 1.281 to 16.866 | 0.15 | 2.04 |
| Pritchard, 2016 | 692 | 6.214 | 4.533 to 8.279 | 2.05 | 3.76 |
| Na, 2017 | 799 | 2.378 | 1.438 to 3.689 | 2.37 | 3.79 |
| Antonarakis, 2018 | 172 | 3.488 | 1.291 to 7.438 | 0.51 | 3.14 |
| Carneiro, 2018 | 1534 | 1.565 | 1.005 to 2.319 | 4.54 | 3.90 |
| Nicolosi, 2019 | 3607 | 5.739 | 5.002 to 6.548 | 10.67 | 3.97 |
| Wei, 2019 | 316 | 6.962 | 4.414 to 10.351 | 0.94 | 3.49 |
| Castro, 2019 | 419 | 4.296 | 2.566 to 6.705 | 1.24 | 3.60 |
| Giri, 2019 | 1328 | 5.572 | 4.400 to 6.945 | 3.93 | 3.88 |
| Sonpavde, 2019 | 514 | 10.117 | 7.648 to 13.055 | 1.52 | 3.68 |
| Sztupinszki, 2020 | 240 | 2.917 | 1.181 to 5.917 | 0.71 | 3.35 |
| Pritzlaff, 2020 | 277 | 4.693 | 2.522 to 7.892 | 0.82 | 3.42 |
| Mateo, 2020 | 175 | 9.714 | 5.761 to 15.098 | 0.52 | 3.15 |
| Momozawa, 2020 | 7636 | 1.270 | 1.031 to 1.547 | 22.59 | 4.00 |
| Mota, 2020 | 64 | 1.562 | 0.0396 to 8.401 | 0.19 | 2.30 |
| Nguyen-Dumont, 2021 | 833 | 2.881 | 1.855 to 4.257 | 2.47 | 3.80 |
| Zhu, 2021 | 1836 | 4.684 | 3.763 to 5.753 | 5.43 | 3.92 |
| Truong, 2022 | 1883 | 4.514 | 3.621 to 5.552 | 5.57 | 3.92 |
| Kimura, 2022 | 549 | 3.825 | 2.383 to 5.788 | 1.63 | 3.70 |
| Brady, 2022 | 437 | 1.144 | 0.373 to 2.650 | 1.30 | 3.62 |
| So, 2022 | 120 | 1.667 | 0.202 to 5.891 | 0.36 | 2.87 |
| Swami, 2022 | 7707 | 7.967 | 7.372 to 8.594 | 22.80 | 4.00 |
| Lee, 2022 | 151 | 9.934 | 5.667 to 15.855 | 0.45 | 3.05 |
| Total (fixed effects) | 33,784 | 4.174 | 3.964 to 4.393 | 100.00 | 100.00 |
| Total (random effects) | 33,784 | 4.466 | 3.376 to 5.700 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 632.0792 |
| DF | 28 |
| Significance level | p < 0.0001 |
| I2 (inconsistency) | 95.57% |
| 95% CI for I2 | 94.50 to 96.43 |
Publication bias
| Egger’s test | |
| Intercept | 0.4449 |
| 95% CI | −2.6280 to 3.5179 |
| Significance level | p = 0.7687 |
| Begg’s test | |
| Kendall’s Tau | 0.03941 |
| Significance level | p = 0.7641 |
Table A7.
Meta-analysis: proportion of metastatic PC patients with somatic BRCA1 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Robinson, 2015 | 150 | 0.667 | 0.0169 to 3.658 | 10.86 | 10.86 |
| Mateo, 2015 | 49 | 2.041 | 0.0517 to 10.854 | 3.60 | 3.60 |
| Mota, 2020 | 64 | 0.000 | 0.000 to 5.601 | 4.68 | 4.68 |
| Tukachinsky, 2021 | 837 | 1.075 | 0.493 to 2.031 | 60.29 | 60.29 |
| Martinez Chanza, 2021 | 141 | 0.709 | 0.0180 to 3.888 | 10.22 | 10.22 |
| Uemura, 2022 | 143 | 0.699 | 0.0177 to 3.835 | 10.36 | 10.36 |
| Total (fixed effects) | 1384 | 1.096 | 0.618 to 1.794 | 100.00 | 100.00 |
| Total (random effects) | 1384 | 1.096 | 0.616 to 1.710 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 1.4171 |
| DF | 5 |
| Significance level | p = 0.9224 |
| I2 (inconsistency) | 0.00% |
| 95% CI for I2 | 0.00 to 13.04 |
Publication bias
| Egger’s test | |
| Intercept | 0.01503 |
| 95% CI | −1.4005 to 1.4305 |
| Significance level | p = 09779 |
| Begg’s test | |
| Kendall’s Tau | 0.06667 |
| Significance level | p = 0.8510 |
Table A8.
Meta-analysis: proportion of metastatic PC patients with somatic BRCA2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Robinson, 2015 | 150 | 12.000 | 7.269 to 18.301 | 10.86 | 16.64 |
| Mateo, 2015 | 49 | 14.286 | 5.942 to 27.242 | 3.60 | 7.26 |
| Mota, 2020 | 64 | 9.375 | 3.519 to 19.297 | 4.68 | 9.02 |
| Tukachinsky, 2021 | 837 | 7.527 | 5.832 to 9.528 | 60.29 | 34.95 |
| Martinez Chanza, 2021 | 141 | 9.929 | 5.535 to 16.098 | 10.22 | 15.99 |
| Uemura, 2022 | 143 | 12.587 | 7.634 to 19.162 | 10.36 | 16.14 |
| Total (fixed effects) | 1384 | 9.161 | 7.696 to 10.802 | 100.00 | 100.00 |
| Total (random effects) | 1384 | 10.256 | 7.921 to 12.854 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 8.1196 |
| DF | 5 |
| Significance level | p = 0.1498 |
| I2 (inconsistency) | 38.42% |
| 95% CI for I2 | 0.00 to 75.53 |
Publication bias
| Egger’s test | |
| Intercept | 2.1365 |
| 95% CI | 0.4976 to 3.7754 |
| Significance level | p = 0.0224 |
| Begg’s test | |
| Kendall’s Tau | 0.06667 |
| Significance level | p = 0.8510 |
Table A9.
Meta-analysis: proportion of metastatic PC patients with somatic BRCA1/2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Robinson, 2015 | 150 | 12.667 | 7.801 to 19.072 | 10.86 | 15.82 |
| Mateo, 2015 | 49 | 16.327 | 7.322 to 29.657 | 3.60 | 6.40 |
| Mota, 2020 | 64 | 9.375 | 3.519 to 19.297 | 4.68 | 8.05 |
| Tukachinsky, 2021 | 837 | 8.602 | 6.791 to 10.710 | 60.29 | 39.34 |
| Martinez Chanza, 2021 | 141 | 10.638 | 6.078 to 16.939 | 10.22 | 15.12 |
| Uemura, 2022 | 143 | 13.287 | 8.193 to 19.969 | 10.36 | 15.28 |
| Total (fixed effects) | 1384 | 10.115 | 8.580 to 11.822 | 100.00 | 100.00 |
| Total (random effects) | 1384 | 10.940 | 8.732 to 13.364 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 7.0496 |
| DF | 5 |
| Significance level | p = 0.2170 |
| I2 (inconsistency) | 29.07% |
| 95% CI for I2 | 0.00 to 70.93 |
Publication bias
| Egger’s test | |
| Intercept | 1.9127 |
| 95% CI | 0.2041 to 3.6213 |
| Significance level | p = 0.0359 |
| Begg’s test | |
| Kendall’s Tau | 0.3333 |
| Significance level | p = 0.3476 |
Table A10.
Meta-analysis: proportion of metastatic PC patients with germline BRCA1 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Gallagher, 2012 | 88 | 3.409 | 0.709 to 9.641 | 2.24 | 8.49 |
| Robinson, 2015 | 150 | 0.667 | 0.0169 to 3.658 | 3.80 | 9.81 |
| Mateo, 2015 | 49 | 0.000 | 0.000 to 7.252 | 1.26 | 6.77 |
| Pritchard, 2016 | 692 | 0.867 | 0.319 to 1.878 | 17.44 | 11.87 |
| Antonarakis, 2018 | 172 | 0.581 | 0.0147 to 3.197 | 4.35 | 10.09 |
| Carneiro, 2018 | 1534 | 0.000 | 0.000 to 0.240 | 38.64 | 12.26 |
| Sonpavde, 2019 | 514 | 5.058 | 3.331 to 7.324 | 12.96 | 11.63 |
| Mota, 2020 | 64 | 0.000 | 0.000 to 5.601 | 1.64 | 7.58 |
| Kimura, 2022 | 549 | 0.364 | 0.0441 to 1.310 | 13.84 | 11.69 |
| Lee, 2022 | 151 | 0.000 | 0.000 to 2.413 | 3.83 | 9.82 |
| Total (fixed effects) | 3963 | 0.583 | 0.371 to 0.873 | 100.00 | 100.00 |
| Total (random effects) | 3963 | 0.935 | 0.192 to 2.229 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 80.7401 |
| DF | 9 |
| Significance level | p < 0.0001 |
| I2 (inconsistency) | 88.85% |
| 95% CI for I2 | 81.60 to 93.25 |
Publication bias
| Egger’s test | |
| Intercept | 1.9459 |
| 95% CI | −2.5292 to 6.4209 |
| Significance level | p = 0.3454 |
| Begg’s test | |
| Kendall’s Tau | 0.1111 |
| Significance level | p = 0.6547 |
Table A11.
Meta-analysis: proportion of metastatic PC patients with germline BRCA2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Gallagher, 2012 | 88 | 4.545 | 1.252 to 11.231 | 2.24 | 7.64 |
| Robinson, 2015 | 150 | 6.000 | 2.780 to 11.084 | 3.80 | 9.45 |
| Mateo, 2015 | 49 | 6.122 | 1.281 to 16.866 | 1.26 | 5.60 |
| Pritchard, 2016 | 692 | 5.347 | 3.792 to 7.295 | 17.44 | 12.87 |
| Antonarakis, 2018 | 172 | 2.907 | 0.950 to 6.653 | 4.35 | 9.87 |
| Carneiro, 2018 | 1534 | 1.565 | 1.005 to 2.319 | 38.64 | 13.62 |
| Sonpavde, 2019 | 514 | 5.058 | 3.331 to 7.324 | 12.96 | 12.43 |
| Mota, 2020 | 64 | 1.562 | 0.0396 to 8.401 | 1.64 | 6.51 |
| Kimura, 2022 | 549 | 3.461 | 2.096 to 5.352 | 13.84 | 12.54 |
| Lee, 2022 | 151 | 9.934 | 5.667 to 15.855 | 3.83 | 9.47 |
| Total (fixed effects) | 3963 | 3.439 | 2.894 to 4.054 | 100.00 | 100.00 |
| Total (random effects) | 3963 | 4.514 | 2.932 to 6.418 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 48.7604 |
| DF | 9 |
| Significance level | p < 0.0001 |
| I2 (inconsistency) | 81.54% |
| 95% CI for I2 | 67.17 to 89.62 |
Publication bias
| Egger’s test | |
| Intercept | 2.5522 |
| 95% CI | −0.4949 to 5.5992 |
| Significance level | p = 0.0895 |
| Begg’s test | |
| Kendall’s Tau | −0.02222 |
| Significance level | p = 0.9287 |
Table A12.
Meta-analysis: proportion of metastatic PC patients with germline BRCA1/2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Gallagher, 2012 | 88 | 7.955 | 3.258 to 15.705 | 0.76 | 7.55 |
| Robinson, 2015 | 150 | 6.667 | 3.243 to 11.918 | 1.29 | 8.71 |
| Mateo, 2015 | 49 | 6.122 | 1.281 to 16.866 | 0.43 | 6.02 |
| Pritchard, 2016 | 692 | 6.214 | 4.533 to 8.279 | 5.93 | 10.54 |
| Antonarakis, 2018 | 172 | 3.488 | 1.291 to 7.438 | 1.48 | 8.97 |
| Carneiro, 2018 | 1534 | 1.565 | 1.005 to 2.319 | 13.14 | 10.89 |
| Sonpavde, 2019 | 514 | 10.117 | 7.648 to 13.055 | 4.41 | 10.33 |
| Mota, 2020 | 64 | 1.562 | 0.0396 to 8.401 | 0.56 | 6.74 |
| Kimura, 2022 | 549 | 3.825 | 2.383 to 5.788 | 4.71 | 10.38 |
| Swami, 2022 | 7707 | 7.967 | 7.372 to 8.594 | 65.99 | 11.13 |
| Lee, 2022 | 151 | 9.934 | 5.667 to 15.855 | 1.30 | 8.73 |
| Total (fixed effects) | 11,670 | 6.561 | 6.119 to 7.026 | 100.00 | 100.00 |
| Total (random effects) | 11,670 | 5.842 | 3.721 to 8.405 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 156.4338 |
| DF | 10 |
| Significance level | p < 0.0001 |
| I2 (inconsistency) | 93.61% |
| 95% CI for I2 | 90.42 to 95.73 |
Publication bias
| Egger’s test | |
| Intercept | −1.2792 |
| 95% CI | −5.3286 to 2.7702 |
| Significance level | p = 0.4930 |
| Begg’s test | |
| Kendall’s Tau | −0.01818 |
| Significance level | p = 0.9379 |
Table A13.
Meta-analysis: proportion of mCRPC patients with somatic BRCA1 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Robinson, 2015 | 150 | 0.667 | 0.0169 to 3.658 | 12.10 | 12.10 |
| Mateo, 2015 | 49 | 2.041 | 0.0517 to 10.854 | 4.01 | 4.01 |
| Mota, 2020 | 64 | 0.000 | 0.000 to 5.601 | 5.21 | 5.21 |
| Tukachinsky, 2021 | 837 | 1.075 | 0.493 to 2.031 | 67.15 | 67.15 |
| Uemura, 2022 | 143 | 0.699 | 0.0177 to 3.835 | 11.54 | 11.54 |
| Total (fixed effects) | 1243 | 1.104 | 0.601 to 1.853 | 100.00 | 100.00 |
| Total (random effects) | 1243 | 1.104 | 0.600 to 1.758 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 1.4098 |
| DF | 4 |
| Significance level | p = 0.8425 |
| I2 (inconsistency) | 0.00% |
| 95% CI for I2 | 0.00 to 44.46 |
Publication bias
| Egger’s test | |
| Intercept | 0.03864 |
| 95% CI | −1.9079 to 1.9852 |
| Significance level | p = 0.9536 |
| Begg’s test | |
| Kendall’s Tau | 0.0000 |
| Significance level | p = 1.0000 |
Table A14.
Meta-analysis: proportion of mCRPC patients with somatic BRCA2 mutation.
| Study | Sample size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Robinson, 2015 | 150 | 12.000 | 7.269 to 18.301 | 12.10 | 20.83 |
| Mateo, 2015 | 49 | 14.286 | 5.942 to 27.242 | 4.01 | 10.15 |
| Mota, 2020 | 64 | 9.375 | 3.519 to 19.297 | 5.21 | 12.33 |
| Tukachinsky, 2021 | 837 | 7.527 | 5.832 to 9.528 | 67.15 | 36.38 |
| Uemura, 2022 | 143 | 12.587 | 7.634 to 19.162 | 11.54 | 20.32 |
| Total (fixed effects) | 1243 | 9.045 | 7.512 to 10.775 | 100.00 | 100.00 |
| Total (random effects) | 1243 | 10.523 | 7.635 to 13.812 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 7.9212 |
| DF | 4 |
| Significance level | p = 0.0945 |
| I2 (inconsistency) | 49.50% |
| 95% CI for I2 | 0.00 to 81.49 |
Publication bias
| Egger’s test | |
| Intercept | 2.2040 |
| 95% CI | −0.01351 to 4.4216 |
| Significance level | p = 0.0508 |
| Begg’s test | |
| Kendall’s Tau | 0.2000 |
| Significance level | p = 0.6242 |
Table A15.
Meta-analysis: proportion of mCRPC patients with somatic BRCA1/2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Robinson, 2015 | 150 | 12.667 | 7.801 to 19.072 | 12.10 | 20.28 |
| Mateo, 2015 | 49 | 16.327 | 7.322 to 29.657 | 4.01 | 9.23 |
| Mota, 2020 | 64 | 9.375 | 3.519 to 19.297 | 5.21 | 11.37 |
| Tukachinsky, 2021 | 837 | 8.602 | 6.791 to 10.710 | 67.15 | 39.41 |
| Uemura, 2022 | 143 | 13.287 | 8.193 to 19.969 | 11.54 | 19.71 |
| Total (fixed effects) | 1243 | 10.026 | 8.415 to 11.828 | 100.00 | 100.00 |
| Total (random effects) | 1243 | 11.263 | 8.485 to 14.378 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 6.9426 |
| DF | 4 |
| Significance level | p = 0.1390 |
| I2 (inconsistency) | 42.38% |
| 95% CI for I2 | 0.00 to 78.81 |
Publication bias
| Egger’s test | |
| Intercept | 1.9919 |
| 95% CI | −0.3078 to 4.2916 |
| Significance level | p = 0.0704 |
| Begg’s test | |
| Kendall’s Tau | 0.6000 |
| Significance level | p = 0.1416 |
Table A16.
Meta-analysis: proportion of mCRPC patients with germline BRCA1 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Gallagher, 2012 | 88 | 3.409 | 0.709 to 9.641 | 3.45 | 13.51 |
| Robinson, 2015 | 150 | 0.667 | 0.0169 to 3.658 | 5.86 | 14.67 |
| Mateo, 2015 | 49 | 0.000 | 0.000 to 7.252 | 1.94 | 11.75 |
| Antonarakis, 2018 | 172 | 0.581 | 0.0147 to 3.197 | 6.71 | 14.90 |
| Carneiro, 2018 | 1534 | 0.000 | 0.000 to 0.240 | 59.54 | 16.49 |
| Sonpavde, 2019 | 514 | 5.058 | 3.331 to 7.324 | 19.98 | 16.06 |
| Mota, 2020 | 64 | 0.000 | 0.000 to 5.601 | 2.52 | 12.62 |
| Total (fixed effects) | 2571 | 0.562 | 0.311 to 0.934 | 100.00 | 100.00 |
| Total (random effects) | 2571 | 1.207 | 0.0526 to 3.839 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 78.5852 |
| DF | 6 |
| Significance level | p < 0.0001 |
| I2 (inconsistency) | 92.36% |
| 95% CI for I2 | 86.81 to 95.58 |
Publication bias
| Egger’s test | |
| Intercept | 2.4198 |
| 95% CI | −3.9590 to 8.7987 |
| Significance level | p = 0.3743 |
| Begg’s test | |
| Kendall’s Tau | −0.04762 |
| Significance level | p = 0.8806 |
Table A17.
Meta-analysis: proportion of mCRPC patients with germline BRCA2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Gallagher, 2012 | 88 | 4.545 | 1.252 to 11.231 | 3.45 | 11.73 |
| Robinson, 2015 | 150 | 6.000 | 2.780 to 11.084 | 5.86 | 14.50 |
| Mateo, 2015 | 49 | 6.122 | 1.281 to 16.866 | 1.94 | 8.60 |
| Antonarakis, 2018 | 172 | 2.907 | 0.950 to 6.653 | 6.71 | 15.16 |
| Carneiro, 2018 | 1534 | 1.565 | 1.005 to 2.319 | 59.54 | 20.91 |
| Sonpavde, 2019 | 514 | 5.058 | 3.331 to 7.324 | 19.98 | 19.09 |
| Mota, 2020 | 64 | 1.562 | 0.0396 to 8.401 | 2.52 | 10.01 |
| Total (fixed effects) | 2571 | 2.691 | 2.101 to 3.391 | 100.00 | 100.00 |
| Total (random effects) | 2571 | 3.895 | 2.132 to 6.158 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 25.7604 |
| DF | 6 |
| Significance level | p = 0.0002 |
| I2 (inconsistency) | 76.71% |
| 95% CI for I2 | 51.20 to 88.88 |
Publication bias
| Egger’s test | |
| Intercept | 2.2629 |
| 95% CI | −0.7550 to 5.2808 |
| Significance level | p = 0.1118 |
| Begg’s test | |
| Kendall’s Tau | 0.04762 |
| Significance level | p = 0.8806 |
Table A18.
Meta-analysis: proportion of mCRPC patients with germline BRCA1/2 mutation.
| Study | Sample Size | Proportion (%) | 95% CI | Weight (%) | |
|---|---|---|---|---|---|
| Fixed | Random | ||||
| Gallagher, 2012 | 88 | 7.955 | 3.258 to 15.705 | 3.45 | 13.42 |
| Robinson, 2015 | 150 | 6.667 | 3.243 to 11.918 | 5.86 | 14.68 |
| Mateo, 2015 | 49 | 6.122 | 1.281 to 16.866 | 1.94 | 11.54 |
| Antonarakis, 2018 | 172 | 3.488 | 1.291 to 7.438 | 6.71 | 14.94 |
| Carneiro, 2018 | 1534 | 1.565 | 1.005 to 2.319 | 59.54 | 16.72 |
| Sonpavde, 2019 | 514 | 10.117 | 7.648 to 13.055 | 19.98 | 16.23 |
| Mota, 2020 | 64 | 1.562 | 0.0396 to 8.401 | 2.52 | 12.46 |
| Total (fixed effects) | 2571 | 3.500 | 2.824 to 4.283 | 100.00 | 100.00 |
| Total (random effects) | 2571 | 5.255 | 2.177 to 9.569 | 100.00 | 100.00 |
Test for heterogeneity
| Q | 71.1738 |
| DF | 6 |
| Significance level | p < 0.0001 |
| I2 (inconsistency) | 91.57% |
| 95% CI for I2 | 85.20 to 95.20 |
Publication bias
| Egger’s test | |
| Intercept | 2.8014 |
| 95% CI | −2.9857 to 8.5884 |
| Significance level | p = 0.2685 |
| Begg’s test | |
| Kendall’s Tau | 0.04762 |
| Significance level | p = 0.8806 |
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Figure 1.
PRISMA diagram.
Figure 2.
Proportion of patients with prostate cancer harboring the BRCA1 mutation. (a) Proportion of patients with any stage PC with the germline BRCA1 mutation; (b) proportion of patients with any stage PC with the somatic BRCA1 mutation; (c) proportion of patients with metastatic PC with the germline BRCA1 mutation; (d) proportion of patients with metastatic PC with the somatic BRCA1 mutation; (e) proportion of patients with mCRPC with the germline BRCA1 mutation; and (f) proportion of patients with mCRPC with the somatic BRCA1 mutation [12,13,14,15,16,18,19,20,22,23,24,25,26,27,28,29,30,31,32,33,34,37,38,39,40,41,42,44,45,46,47,48,49,50,51].
Figure 2.
Proportion of patients with prostate cancer harboring the BRCA1 mutation. (a) Proportion of patients with any stage PC with the germline BRCA1 mutation; (b) proportion of patients with any stage PC with the somatic BRCA1 mutation; (c) proportion of patients with metastatic PC with the germline BRCA1 mutation; (d) proportion of patients with metastatic PC with the somatic BRCA1 mutation; (e) proportion of patients with mCRPC with the germline BRCA1 mutation; and (f) proportion of patients with mCRPC with the somatic BRCA1 mutation [12,13,14,15,16,18,19,20,22,23,24,25,26,27,28,29,30,31,32,33,34,37,38,39,40,41,42,44,45,46,47,48,49,50,51].
Figure 3.
Proportion of patients with prostate cancer harboring the BRCA2 mutation. (a) Proportion of patients with any stage PC with the germline BRCA2 mutation; (b) proportion of patients with any stage PC with the somatic BRCA2 mutation; (c) proportion of patients with metastatic PC with the germline BRCA2 mutation; (d) proportion of patients with metastatic PC with the somatic BRCA2 mutation; (e) proportion of patients with mCRPC with the germline BRCA2 mutation; and (f) proportion of patients with mCRPC with the somatic BRCA2 mutation [12,13,15,16,17,18,19,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51].
Figure 3.
Proportion of patients with prostate cancer harboring the BRCA2 mutation. (a) Proportion of patients with any stage PC with the germline BRCA2 mutation; (b) proportion of patients with any stage PC with the somatic BRCA2 mutation; (c) proportion of patients with metastatic PC with the germline BRCA2 mutation; (d) proportion of patients with metastatic PC with the somatic BRCA2 mutation; (e) proportion of patients with mCRPC with the germline BRCA2 mutation; and (f) proportion of patients with mCRPC with the somatic BRCA2 mutation [12,13,15,16,17,18,19,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51].
Figure 4.
Proportion of patients with prostate cancer harboring any BRCA mutation. (a) Proportion of patients with any stage PC with the germline BRCA1/2 mutation; (b) proportion of patients with any stage PC with the somatic BRCA1/2 mutation; (c) proportion of patients with metastatic PC with the germline BRCA1/2 mutation; (d) proportion of patients with metastatic PC with the somatic BRCA1/2 mutation; (e) proportion of patients with mCRPC with the germline BRCA1/2 mutation; and (f) proportion of patients with mCRPC with the somatic BRCA1/2 mutation [12,13,15,16,19,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51].
Figure 4.
Proportion of patients with prostate cancer harboring any BRCA mutation. (a) Proportion of patients with any stage PC with the germline BRCA1/2 mutation; (b) proportion of patients with any stage PC with the somatic BRCA1/2 mutation; (c) proportion of patients with metastatic PC with the germline BRCA1/2 mutation; (d) proportion of patients with metastatic PC with the somatic BRCA1/2 mutation; (e) proportion of patients with mCRPC with the germline BRCA1/2 mutation; and (f) proportion of patients with mCRPC with the somatic BRCA1/2 mutation [12,13,15,16,19,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51].
Table 1.
Summary of the results of the meta-analysis.
| BRCA1 | BRCA2 | BRCA1/2 | ||||
|---|---|---|---|---|---|---|
| Germline | Somatic | Germline | Somatic | Germline | Somatic | |
| Patients with any stage PC | ||||||
| Number of studies | 31 | 10 | 30 | 10 | 29 | 10 |
| Number of patients | 32,525 | 3229 | 29,813 | 3229 | 33,784 | 3229 |
| % (fixed effect) | 0.53 (95% CI: 0.45–0.62) | 1.20 (95% CI: 0.85–1.64) | 2.47 (95% CI: 2.30–2.66) | 4.77 (95% CI: 4.06–5.56) | 4.17 (95% CI: 3.96–4.39) | 6.07 (95% CI: 5.27–6.95) |
| % (random effect) | 0.73 (95% CI: 0.51–1.00) | 1.20 (95% CI: 0.85–1.60) | 3.25 (95% CI: 2.54–4.04) | 6.29 (95% CI: 3.79–9.38) | 4.47 (95% CI: 3.38–5.70) | 7.18 (95% CI: 4.89–9.87) |
| Heterogeneity I2 (p-value) | 81.19% (p < 0.0001) | 0.00% (p = 0.7423) | 90.96% (p < 0.0001) | 89.14% (p < 0.0001) | 95.57% (p < 0.0001) | 84.17% (p < 0.0001) |
| Metastatic PC patients | ||||||
| Number of studies | 10 | 6 | 10 | 6 | 11 | 6 |
| Number of patients | 3963 | 1384 | 3963 | 1384 | 11,670 | 1384 |
| % (fixed effect) | 0.58 (95% CI: 0.37–0.87) | 1.10 (95% CI: 0.62–1.79) | 3.44 (95% CI: 2.89–4.05) | 9.16 (95% CI: 7.70–10.80) | 6.56 (95% CI: 6.12–7.03) | 10.12 (95% CI: 8.58–11.82) |
| % (random effect) | 0.94 (95% CI: 0.19–2.23) | 1.10 (95% CI: 0.62–1.71) | 4.51 (95% CI: 2.93–6.42) | 10.26 (95% CI: 7.92–12.85) | 5.84 (95% CI: 3.72–8.41) | 10.94 (95% CI: 8.73–13.36) |
| Heterogeneity I2 (p-value) | 88.85% (p < 0.0001) | 0.00% (p = 0.9224) | 81.54% (p < 0.0001) | 38.42% (p = 0.1498) | 93.61% (p < 0.0001) | 29.07% (p = 0.2170) |
| mCRPC patients | ||||||
| Number of studies | 7 | 5 | 7 | 5 | 7 | 5 |
| Number of patients | 2571 | 1243 | 2571 | 1243 | 2571 | 1243 |
| % (fixed effect) | 0.56 (95% CI: 0.31–0.93) | 1.10 (95% CI: 0.60–1.85) | 2.69 (95% CI: 2.10–3.39) | 9.05 (95% CI: 7.51–10.78) | 3.50 (95% CI: 2.82–4.28) | 10.03 (95% CI: 8.42–11.83) |
| % (random effect) | 1.21 (95% CI: 0.05–3.84) | 1.10 (95% CI: 0.60–1.76) | 3.90 (95% CI: 2.13–6.16) | 10.52 (95% CI: 7.64–13.81) | 5.26 (95% CI: 2.18–9.57) | 11.26 (95% CI: 8.49–14.38) |
| Heterogeneity I2 (p-value) | 92.36% (p < 0.0001) | 0.00% (p = 0.8425) | 76.71% (p = 0.0002) | 49.50% (p = 0.0945) | 91.57% (p < 0.0001) | 42.38% (p = 0.1390) |
PC: prostate cancer; mCRPC: metastatic castration-resistant prostate cancer; CI: confidence interval.
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Valsecchi, A.A.; Dionisio, R.; Panepinto, O.; Paparo, J.; Palicelli, A.; Vignani, F.; Di Maio, M. Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis. Cancers 2023, 15, 2435. https://doi.org/10.3390/cancers15092435
AMA Style
Valsecchi AA, Dionisio R, Panepinto O, Paparo J, Palicelli A, Vignani F, Di Maio M. Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis. Cancers. 2023; 15(9):2435. https://doi.org/10.3390/cancers15092435
Chicago/Turabian StyleValsecchi, Anna Amela, Rossana Dionisio, Olimpia Panepinto, Jessica Paparo, Andrea Palicelli, Francesca Vignani, and Massimo Di Maio. 2023. "Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis" Cancers 15, no. 9: 2435. https://doi.org/10.3390/cancers15092435
APA StyleValsecchi, A. A., Dionisio, R., Panepinto, O., Paparo, J., Palicelli, A., Vignani, F., & Di Maio, M. (2023). Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis. Cancers, 15(9), 2435. https://doi.org/10.3390/cancers15092435
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