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The influence of BRCA2 mutation on localized prostate cancer

Abstract

A key challenge in the management of localized prostate cancer is the identification of men with a high likelihood of progression to an advanced, incurable stage. Patients who harbour germline BRCA2 mutations have worse clinical outcomes than noncarriers when treated with surgery or radiotherapy. Insights from different disciplines have improved our understanding of why patients with BRCA2-mutant tumours have a high likelihood of failing on conventional management after diagnosis. Treatment-naive BRCA2-mutant tumours are defined by aggressive clinical and molecular features early in the disease course, and the genomic landscape of these BRCA2-mutant tumours is characterized by a unique molecular profile and higher genomic instability than noncarrier tumours. Moreover, BRCA2-mutant tumours commonly show the concurrent presence of the intraductal carcinoma of the prostate (IDCP) pathology, a poor prognostic indicator. Subclonal analyses have revealed that IDCP and invasive adenocarcinoma in BRCA2-mutant tumours can arise from the same ancestral clone, implying that a temporal evolutionary trajectory exists. Finally, functional studies have shown that BRCA2-mutant tumours can harbour a subpopulation of cancer cells that can tolerate castration de novo, enabling the tumour to evade androgen deprivation therapy. Importantly, future challenges remain regarding how to best model the biology underpinning this aggressive phenotype and translate these findings to improve clinical outcomes.

Key points

  • Patients with prostate cancer who harbour germline BRCA2 mutations have worse clinical outcomes than noncarriers when treated with surgery or radiotherapy.

  • BRCA2-mutant tumours have a unique somatic molecular profile, including increased genomic instability, relative to noncarrier tumours.

  • BRCA2-mutant tumours commonly show the concurrent presence of intraductal carcinoma of the prostate (IDCP) pathology, which is a poor prognostic indicator.

  • Subclonal analyses have revealed that IDCP and invasive adenocarcinoma in BRCA2-mutant tumours arise from the same ancestral clone, suggesting the existence of a temporal evolutionary trajectory.

  • BRCA2-mutant tumours can harbour a subpopulation of tumour cells that can tolerate castration de novo, which allows the tumour to evade androgen deprivation therapy.

  • Future challenges remain in modelling the biology underpinning the aggressive phenotype of BRCA2-mutant tumours and translating these findings in order to improve clinical outcomes.

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Fig. 1: Molecular features of sporadic and germline BRCA2-mutant localized prostate cancer.
Fig. 2: Concurrent IDCP in a BRCA2-mutant PDX model.
Fig. 3: Castration-tolerant BRCA2-mutant tumour cell subpopulations.

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Acknowledgements

The authors thank L. Porter and M. Lawrence for helpful discussions and contributions to figures. This work was supported by funding from the National Health and Medical Research Council of Australia (fellowship to G.P.R. 1102752, project grant 1077799), the Victorian Government through the Victorian Cancer Agency (fellowship to R.A.T. MCRF15023 and the CAPTIV programme), the EJ Whitten Foundation, the Peter and Lyndy White Foundation and TissuPath Pathology.

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R.A.T., M.F., R.J.R., P.C.B., R.G.B. and G.P.R. researched data for the article. R.A.T., M.F., D.G.M., R.G.B. and G.P.R. made substantial contributions to discussion of the article contents. All authors wrote the manuscript and reviewed and/or edited the manuscript before submission.

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Correspondence to Gail P. Risbridger.

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Taylor, R.A., Fraser, M., Rebello, R.J. et al. The influence of BRCA2 mutation on localized prostate cancer. Nat Rev Urol 16, 281–290 (2019). https://doi.org/10.1038/s41585-019-0164-8

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