Implications of High Rates of Metastatic Prostate Cancer in<i>BRCA2</i>Mutation Carriers

Gleicher, Stephanie; Kauffman, Eric; Kotula, Leszek; Bratslavsky, Gennady; Vourganti, Srinivas

doi:10.1002/pros.23204

Cited by 8 publications

(10 citation statements)

References 30 publications

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“…2b), and high expression of LIMK1 in prostate cancer indicates a poor outcome [23]. Germline DDR mutations, especially loss-of function BRCA2 mutations, are found primarily in prostate cancer presenting a more aggressive phenotype and a poor prognosis [24]. In our study, we found germline mutations in BRCA2, ATM, CHEK2, RAD50, and RAD50D, among which BRCA2 (5/7) harbored the most frequent germline mutation.…”

Section: Dna Damage Repair Pathwaysupporting

confidence: 48%

TP53 alterations of hormone-naïve prostate cancer in the Chinese population

Liu

Guo

Zhu

et al. 2020

Prostate Cancer Prostatic Dis

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Background Prostate cancer (PCa) shows racial disparity in clinical and genomic characteristics, and Asian patients with PCa often present with more aggressive phenotypes at diagnosis. The ability of TP53 to serve as a prognostic biomarker of PCa has been well studied in Western populations. However, no studies to date have examined the role of TP53 in the disparities of primary hormone-naïve prostate cancer (HNPC) between Chinese and Western populations. Methods We collected prostate tumors and matched normal tissues or blood samples to perform targeted next-generation sequencing of 94 Chinese primary localized HNPC samples, and correlated these genomic profiles with clinical outcomes. The OncoKB knowledge database was used to identify and classify actionable alterations. Results The aberrations of PTEN, CDK12, and SPOP in Chinese HNPC samples were similar to those in the Western samples. However, we demonstrated an association of a high frequency of TP53 alterations (21/94) with a relatively higher percentage of alterations in the Wnt signaling pathway (15/94) in Chinese HNPC. Additionally, we highlighted alterations of LRP1B as accounting for a high proportion of PCa and found more frequent alterations in CDH1 in Chinese PCa. Of these, only CDH1 alteration was associated with rapid biochemical recurrence (BCR). However, we verified that TP53 status was at the core of the genomic alteration landscape in Chinese HNPC with putative driver mutations because of the strong connections with other signaling pathways. The mutually exclusive relationship between alterations in TP53 and Wnt/ CTNNB1 further molecularly characterizes subsets of prostate cancers. Moreover, the alteration of KMT2C was more likely to co-occur with TP53 alteration, indicating a more aggressive phenotype of PCa, which was associated with sensitivity to treatment with poly ADT-ribose polymerase (PARP) inhibitors. Conclusions Detection of TP53 alterations has clinical utility for guiding precision cancer therapy for HNPC, especially in the Chinese population.

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Section: Dna Damage Repair Pathwaysupporting

confidence: 48%

TP53 alterations of hormone-naïve prostate cancer in the Chinese population

Liu

Guo

Zhu

et al. 2020

Prostate Cancer Prostatic Dis

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“…When compared with non-BRCA2 carriers, BRCA2 carriers had a significantly higher PPV of PSA >3.0 ng/mL (31% vs 18%; p=0.025), a higher PC incidence rate per 1000 person years (19.4 vs 12.0; p=0.03), a significantly higher frequency of intermediate-high risk PC (p=0.011) and were significantly younger at the time of PC diagnosis (p=0.044), with the youngest age of onset being recorded in a 41-year-old BRCA2 carrier. Overall, the results so far from the ongoing IMPACT study further substantiate the earlier age of onset and more aggressive PC phenotype seen in BRCA2 carriers which has been widely reported throughout the literature, 11,[31][32][33][34]36,87 and also highlights the efficacy of using PSA testing in this patient subgroup.…”

Section: Prostate Cancer Screening In Unaffected Brca2 Mutation Carrierssupporting

confidence: 74%

A Case-Based Clinical Approach to the Investigation, Management and Screening of Families with BRCA2 Related Prostate Cancer

King¹,

McHugh²,

Snape³

2021

TACG

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BRCA2 is the most commonly implicated DNA damage repair gene associated with inherited prostate cancer. BRCA2 deficient prostate cancer typically presents at a younger age, is more poorly differentiated, and is associated with worse survival outcomes than non-BRCA2 associated prostate cancer. Despite these unfavourable prognostic implications, poly-ADP ribose polymerase inhibitors and platinum-based chemotherapy have been identified as potent targeted therapeutic agents towards BRCA1/2 deficient cancer cells. This review article explores the literature surrounding BRCA2-related prostate cancer through a familial clinical scenario. The investigation, diagnosis and management of BRCA2 deficient prostate cancer will be explored, alongside the implications of the identification of a germline pathogenic BRCA2 variant within a family, cascade screening and prostate cancer surveillance in unaffected male BRCA2 carriers. A greater understanding of the molecular pathogenesis of DNA damage repair gene deficient prostate cancer, coupled with new treatment paradigms and widened access to both somatic and germline genetic analysis for prostate cancer patients and their families will hopefully enable the robust implementation of high quality evidence-based clinical pathways for both the management and identification of BRCA2 deficient prostate cancer and improved screening, early detection and prevention strategies for individuals at increased genetic risk of prostate cancer.

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“…BRCA1 and BRCA2 gene mutations, confirmed to be linked to breast cancer in families [44, 45], confer a 3.8- and 8.6-fold increased risk of developing prostate cancer, respectively [14, 15]. BRCA2 carriers are associated with poor prognosis and more aggressive form in prostate cancer [46, 47]. In addition to BRCA1 and BRCA2 genes, previous studies supported the contribution of other undetermined genetic factors to the aetiology and prognosis of prostate cancer in breast cancer-prone families [48–50].…”

Section: Discussionmentioning

confidence: 99%

First-degree family history of breast cancer is associated with prostate cancer risk: a systematic review and meta-analysis

et al. 2019

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Background The relationship between first-degree family history of female breast cancer and prostate cancer risk in the general population remains unclear. We performed a meta-analysis to determine the association between first-degree family history of female breast cancer and prostate cancer risk. Methods Databases, including MEDLINE, Embase, and Web of Science, were searched for all associated studies that evaluated associations between first-degree family history of female breast cancer and prostate cancer risk up to December 31, 2018. Information on study characteristics and outcomes were extracted based on the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. The quality of evidence was assessed using the GRADE approach. Results Eighteen studies involving 17,004,892 individuals were included in the meta-analysis. Compared with no family history of female breast cancer, history of female breast cancer in first-degree relatives was associated with an increased risk of prostate cancer [relative risk (RR) 1.18, 95% confidence interval (CI) 1.12–1.25] with moderate-quality evidence. A history of breast cancer in mothers only (RR 1.19, 95% CI 1.10–1.28) and sisters only (RR 1.71, 95% CI 1.43–2.04) was associated with increased prostate cancer risk with moderate-quality evidence. However, a family history of breast cancer in daughters only was not associated with prostate cancer incidence (RR 1.74, 95% CI 0.74–4.12) with moderate-quality evidence. A family history of female breast cancer in first-degree relatives was associated with an 18% increased risk of lethal prostate cancer (95% CI 1.04–1.34) with low-quality evidence. Conclusions This review demonstrates that men with a family history of female breast cancer in first-degree relatives had an increased risk of prostate cancer, including risk of lethal prostate cancer. These findings may guide screening, earlier detection, and treatment of men with a family history of female breast cancer in first-degree relatives.

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Implications of High Rates of Metastatic Prostate Cancer inBRCA2Mutation Carriers

Cited by 8 publications

References 30 publications

TP53 alterations of hormone-naïve prostate cancer in the Chinese population

TP53 alterations of hormone-naïve prostate cancer in the Chinese population

A Case-Based Clinical Approach to the Investigation, Management and Screening of Families with BRCA2 Related Prostate Cancer

First-degree family history of breast cancer is associated with prostate cancer risk: a systematic review and meta-analysis

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