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.
Similar content being viewed by others
References
Attard, G. et al. Prostate cancer. Lancet 387, 70–82 (2016).
Pritchard, C. C. et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 375, 443–453 (2016).
Banks, P., Xu, W., Murphy, D., James, P. & Sandhu, S. Relevance of DNA damage repair in the management of prostate cancer. Curr. Probl. Cancer 41, 287–301 (2017).
Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).
Pritchard, C. C., Offit, K. & Nelson, P. S. DNA-repair gene mutations in metastatic prostate cancer. N. Engl. J. Med. 375, 1804–1805 (2016).
Castro, E. et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J. Clin. Oncol. 31, 1748–1757 (2013).
Risbridger, G. P. et al. Patient-derived xenografts reveal that intraductal carcinoma of the prostate is a prominent pathology in BRCA2 mutation carriers with prostate cancer and correlates with poor prognosis. Eur. Urol. 67, 496–503 (2015).
Castro, E. et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur. Urol. 68, 186–193 (2015).
Taylor, R. A. et al. Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Nat. Commun. 8, 13671 (2017).
Porter, L. H. et al. Intraductal carcinoma of the prostate can evade androgen deprivation, with emergence of castrate-tolerant cells. BJU Int. 121, 971–978 (2018).
D’Amico, A. V. et al. Outcome based staging for clinically localized adenocarcinoma of the prostate. J. Urol. 158, 1422–1426 (1997).
Boutros, P. C. et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat. Genet. 47, 736–745 (2015).
Espiritu, S. M. G. et al. The evolutionary landscape of localized prostate cancers drives clinical aggression. Cell 173, 1003–1013 (2018).
Fraser, M. et al. Genomic hallmarks of localized, non-indolent prostate cancer. Nature 541, 359–364 (2017).
Bancroft, E. K. et al. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. Eur. Urol. 66, 489–499 (2014).
Roobol, M. J. & Carlsson, S. V. Risk stratification in prostate cancer screening. Nat. Rev. Urol. 10, 38–48 (2013).
Mikropoulos, C. et al. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition. Br. J. Cancer 118, 266–276 (2018).
Cheng, H. H., Pritchard, C. C., Montgomery, B., Lin, D. W. & Nelson, P. S. Prostate cancer screening in a new era of genetics. Clin. Genitourin. Cancer 15, 625–628 (2017).
Porter, L. H. et al. Systematic review links the prevalence of intraductal carcinoma of the prostate to prostate cancer risk categories. Eur. Urol. 72, 492–495 (2017).
Murphy, D. G., Risbridger, G. P., Bristow, R. G. & Sandhu, S. The evolving narrative of DNA repair gene defects: distinguishing indolent from lethal prostate cancer. Eur. Urol. 71, 748–749 (2017).
Epstein, J. I. et al. A contemporary prostate cancer grading system: a validated alternative to the gleason score. Eur. Urol. 69, 428–435 (2016).
Truong, M., Frye, T., Messing, E. & Miyamoto, H. Historical and contemporary perspectives on cribriform morphology in prostate cancer. Nat. Rev. Urol. 15, 475–482 (2018).
Guo, C. C. & Epstein, J. I. Intraductal carcinoma of the prostate on needle biopsy: histologic features and clinical significance. Mod. Pathol. 19, 1528–1535 (2006).
Van Der Kwast, T. et al. Biopsy diagnosis of intraductal carcinoma is prognostic in intermediate and high risk prostate cancer patients treated by radiotherapy. Eur. J. Cancer 48, 1318–1325 (2012).
Kato, M. et al. The presence of intraductal carcinoma of the prostate in needle biopsy is a significant prognostic factor for prostate cancer patients with distant metastasis at initial presentation. Mod. Pathol. 29, 166–173 (2016).
Kimura, K. et al. Prognostic value of intraductal carcinoma of the prostate in radical prostatectomy specimens. Prostate 74, 680–687 (2014).
Watts, K., Li, J., Magi-Galluzzi, C. & Zhou, M. Incidence and clinicopathological characteristics of intraductal carcinoma detected in prostate biopsies: a prospective cohort study. Histopathology 63, 574–579 (2013).
Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).
Cooper, C. S. et al. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nat. Genet. 47, 367–372 (2015).
Wedge, D. C. et al. Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets. Nat. Genet. 50, 682–692 (2018).
Baca, S. C. et al. Punctuated evolution of prostate cancer genomes. Cell 153, 666–677 (2013).
Gerhauser, C. et al. Molecular evolution of early-onset prostate cancer identifies molecular risk markers and clinical trajectories. Cancer Cell 34, 996–1011 (2018).
Barbieri, C. E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44, 685–689 (2012).
Tomlins, S. A. et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448, 595–599 (2007).
Hopkins, J. F. et al. Mitochondrial mutations drive prostate cancer aggression. Nat. Commun. 8, 656 (2017).
Ishkanian, A. S. et al. High-resolution array CGH identifies novel regions of genomic alteration in intermediate-risk prostate cancer. Prostate 69, 1091–1100 (2009).
Locke, J. A. et al. NKX3.1 haploinsufficiency is prognostic for prostate cancer relapse following surgery or image-guided radiotherapy. Clin. Cancer Res. 18, 308–316 (2012).
Trudel, D. et al. 4FISH-IF, a four-color dual-gene FISH combined with p63 immunofluorescence to evaluate NKX3.1 and MYC status in prostate cancer. J. Histochem. Cytochem. 61, 500–509 (2013).
Zafarana, G. et al. Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer 118, 4053–4062 (2012).
Antonarakis, E. S., Nakazawa, M. & Luo, J. Resistance to androgen-pathway drugs in prostate cancer. N. Engl. J. Med. 371, 2234 (2014).
Chua, F. Y. & Adams, B. D. Androgen receptor and miR-206 regulation in prostate cancer. Transcription 8, 313–327 (2017).
Hua, J. T. et al. Risk SNP-mediated promoter-enhancer switching drives prostate cancer through lncRNA PCAT19. Cell 174, 564–575 (2018).
Guo, H., Ahmed, M., Hua, J., Soares, F. & He, H. H. Crucial role of noncoding RNA in driving prostate cancer development and progression. Epigenomics 9, 1–3 (2017).
Chen, S. et al. Widespread and functional RNA circularization in localized prostate cancer. Cell 176, 831–843 (2019).
Berger, M. F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).
Lalonde, E. et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol. 15, 1521–1532 (2014).
Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).
Armenia, J. et al. The long tail of oncogenic drivers in prostate cancer. Nat. Genet. 50, 645–651 (2018).
Gerhauser, C. et al. Molecular evolution of early-onset prostate cancer identifies molecular risk markers and clinical trajectories. Cancer Cell 34, 996–1011 (2018).
Castro, E. et al. High burden of copy number alterations and c-MYC amplification in prostate cancer from BRCA2 germline mutation carriers. Ann. Oncol. 26, 2293–2300 (2015).
Hieronymus, H. et al. Copy number alteration burden predicts prostate cancer relapse. Proc. Natl Acad. Sci. USA 111, 11139–11144 (2014).
Chua, M. L. K. et al. A prostate cancer “Nimbosus”: genomic instability and SChLAP1 dysregulation underpin aggression of intraductal and cribriform subpathologies. Eur. Urol. 72, 665–674 (2017).
Bhandari, V. et al. Molecular landmarks of tumor hypoxia across cancer types. Nat. Genet. 51, 308–318 (2019).
Kim, Y. et al. Targeted proteomics identifies liquid-biopsy signatures for extracapsular prostate cancer. Nat. Commun. 7, 11906 (2016).
Kim, Y. et al. Identification of differentially expressed proteins in direct expressed prostatic secretions of men with organ-confined versus extracapsular prostate cancer. Mol. Cell Proteomics 11, 1870–1884 (2012).
Francis, J. C., McCarthy, A., Thomsen, M. K., Ashworth, A. & Swain, A. Brca2 and Trp53 deficiency cooperate in the progression of mouse prostate tumourigenesis. PLOS Genet. 6, e1000995 (2010).
Lawrence, M. G. et al. A preclinical xenograft model of prostate cancer using human tumors. Nat. Protoc. 8, 836–848 (2013).
Risbridger, G. P., Toivanen, R. & Taylor, R. A. Preclinical models of prostate cancer: patient-derived xenografts, organoids, and other explant models. Cold Spring Harb. Perspect. Med. 8, a030536 (2018).
Lawrence, M. G. et al. Establishment of primary patient-derived xenografts of palliative TURP specimens to study castrate-resistant prostate cancer. Prostate 75, 1475–1483 (2015).
Risch, H. A. et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J. Natl Cancer Inst. 98, 1694–1706 (2006).
Chen, Z. et al. The presence and clinical implication of intraductal carcinoma of prostate in metastatic castration resistant prostate cancer. Prostate 75, 1247–1254 (2015).
O’Brien, C. et al. Histologic changes associated with neoadjuvant chemotherapy are predictive of nodal metastases in patients with high-risk prostate cancer. Am. J. Clin. Pathol. 133, 654–661 (2010).
Efstathiou, E. et al. Morphologic characterization of preoperatively treated prostate cancer: toward a post-therapy histologic classification. Eur. Urol. 57, 1030–1038 (2010).
Toivanen, R. et al. A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors. Sci. Transl Med. 5, 187ra171 (2013).
Evans, M. A. et al. Active surveillance of men with low risk prostate cancer: evidence from the Prostate Cancer Outcomes Registry – Victoria. Med. J. Aust. 208, 439–443 (2018).
Bul, M. et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur. Urol. 63, 597–603 (2013).
Lowenstein, L. M. et al. Active surveillance for prostate and thyroid cancers: evolution in clinical paradigms and lessons learned. Nat. Rev. Clin. Oncol. https://doi.org/10.1038/s41571-018-0116-x (2018).
Carter, H. B. et al. Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for prostate cancer. Eur. Urol. https://doi.org/10.1016/j.eururo.2018.09.021 (2018).
Mateo, J. et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373, 1697–1708 (2015).
Gillessen, S. et al. Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015. Ann. Oncol. 26, 1589–1604 (2015).
Artibani, W., Porcaro, A. B., De Marco, V., Cerruto, M. A. & Siracusano, S. Management of biochemical recurrence after primary curative treatment for prostate cancer: a review. Urol. Int. 100, 251–262 (2018).
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41585-019-0164-8
- Springer Nature Limited
This article is cited by
-
Prostate cancer risk, screening and management in patients with germline BRCA1/2 mutations
Nature Reviews Urology (2023)
-
Senescence-associated secretory phenotype constructed detrimental and beneficial subtypes and prognostic index for prostate cancer patients undergoing radical prostatectomy
Discover Oncology (2023)
-
Recent advances in the molecular targeted drugs for prostate cancer
International Urology and Nephrology (2023)
-
Review of Active Surveillance in Underrepresented and High-Risk Populations: Feasibility and Safety
Current Urology Reports (2023)
-
Biomarkers beyond BRCA: promising combinatorial treatment strategies in overcoming resistance to PARP inhibitors
Journal of Biomedical Science (2022)