Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Attard, G. et al. Prostate cancer. Lancet 387, 70–82 (2016).

    Article  Google Scholar 

  2. Pritchard, C. C. et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 375, 443–453 (2016).

    CAS  Article  Google Scholar 

  3. 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).

    Article  Google Scholar 

  4. Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).

    CAS  Article  Google Scholar 

  5. Pritchard, C. C., Offit, K. & Nelson, P. S. DNA-repair gene mutations in metastatic prostate cancer. N. Engl. J. Med. 375, 1804–1805 (2016).

    Article  Google Scholar 

  6. 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).

    CAS  Article  Google Scholar 

  7. 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).

    CAS  Article  Google Scholar 

  8. 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).

    CAS  Article  Google Scholar 

  9. Taylor, R. A. et al. Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Nat. Commun. 8, 13671 (2017).

    CAS  Article  Google Scholar 

  10. 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).

    CAS  Article  Google Scholar 

  11. D’Amico, A. V. et al. Outcome based staging for clinically localized adenocarcinoma of the prostate. J. Urol. 158, 1422–1426 (1997).

    Article  Google Scholar 

  12. Boutros, P. C. et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat. Genet. 47, 736–745 (2015).

    CAS  Article  Google Scholar 

  13. Espiritu, S. M. G. et al. The evolutionary landscape of localized prostate cancers drives clinical aggression. Cell 173, 1003–1013 (2018).

    CAS  Article  Google Scholar 

  14. Fraser, M. et al. Genomic hallmarks of localized, non-indolent prostate cancer. Nature 541, 359–364 (2017).

    CAS  Article  Google Scholar 

  15. 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).

    Article  Google Scholar 

  16. Roobol, M. J. & Carlsson, S. V. Risk stratification in prostate cancer screening. Nat. Rev. Urol. 10, 38–48 (2013).

    CAS  Article  Google Scholar 

  17. 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).

    Article  Google Scholar 

  18. 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).

    Article  Google Scholar 

  19. 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).

    Article  Google Scholar 

  20. 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).

    Article  Google Scholar 

  21. Epstein, J. I. et al. A contemporary prostate cancer grading system: a validated alternative to the gleason score. Eur. Urol. 69, 428–435 (2016).

    Article  Google Scholar 

  22. 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).

    Article  Google Scholar 

  23. 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).

    Article  Google Scholar 

  24. 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).

    Article  Google Scholar 

  25. 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).

    CAS  Article  Google Scholar 

  26. Kimura, K. et al. Prognostic value of intraductal carcinoma of the prostate in radical prostatectomy specimens. Prostate 74, 680–687 (2014).

    Article  Google Scholar 

  27. 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).

    PubMed  Google Scholar 

  28. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).

    Article  Google Scholar 

  29. 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).

    CAS  Article  Google Scholar 

  30. 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).

    CAS  Article  Google Scholar 

  31. Baca, S. C. et al. Punctuated evolution of prostate cancer genomes. Cell 153, 666–677 (2013).

    CAS  Article  Google Scholar 

  32. Gerhauser, C. et al. Molecular evolution of early-onset prostate cancer identifies molecular risk markers and clinical trajectories. Cancer Cell 34, 996–1011 (2018).

    CAS  Article  Google Scholar 

  33. Barbieri, C. E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44, 685–689 (2012).

    CAS  Article  Google Scholar 

  34. Tomlins, S. A. et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448, 595–599 (2007).

    CAS  Article  Google Scholar 

  35. Hopkins, J. F. et al. Mitochondrial mutations drive prostate cancer aggression. Nat. Commun. 8, 656 (2017).

    Article  Google Scholar 

  36. 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).

    CAS  Article  Google Scholar 

  37. 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).

    CAS  Article  Google Scholar 

  38. 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).

    Article  Google Scholar 

  39. 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).

    CAS  Article  Google Scholar 

  40. Antonarakis, E. S., Nakazawa, M. & Luo, J. Resistance to androgen-pathway drugs in prostate cancer. N. Engl. J. Med. 371, 2234 (2014).

    Article  Google Scholar 

  41. Chua, F. Y. & Adams, B. D. Androgen receptor and miR-206 regulation in prostate cancer. Transcription 8, 313–327 (2017).

    CAS  Article  Google Scholar 

  42. Hua, J. T. et al. Risk SNP-mediated promoter-enhancer switching drives prostate cancer through lncRNA PCAT19. Cell 174, 564–575 (2018).

    CAS  Article  Google Scholar 

  43. 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).

    Article  Google Scholar 

  44. Chen, S. et al. Widespread and functional RNA circularization in localized prostate cancer. Cell 176, 831–843 (2019).

    Article  Google Scholar 

  45. Berger, M. F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).

    CAS  Article  Google Scholar 

  46. 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).

    Article  Google Scholar 

  47. Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).

    CAS  Article  Google Scholar 

  48. Armenia, J. et al. The long tail of oncogenic drivers in prostate cancer. Nat. Genet. 50, 645–651 (2018).

    CAS  Article  Google Scholar 

  49. Gerhauser, C. et al. Molecular evolution of early-onset prostate cancer identifies molecular risk markers and clinical trajectories. Cancer Cell 34, 996–1011 (2018).

    CAS  Article  Google Scholar 

  50. 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).

    CAS  Article  Google Scholar 

  51. Hieronymus, H. et al. Copy number alteration burden predicts prostate cancer relapse. Proc. Natl Acad. Sci. USA 111, 11139–11144 (2014).

    CAS  Article  Google Scholar 

  52. 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).

    CAS  Article  Google Scholar 

  53. Bhandari, V. et al. Molecular landmarks of tumor hypoxia across cancer types. Nat. Genet. 51, 308–318 (2019).

    CAS  Article  Google Scholar 

  54. Kim, Y. et al. Targeted proteomics identifies liquid-biopsy signatures for extracapsular prostate cancer. Nat. Commun. 7, 11906 (2016).

    CAS  Article  Google Scholar 

  55. 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).

    Article  Google Scholar 

  56. 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).

    Article  Google Scholar 

  57. Lawrence, M. G. et al. A preclinical xenograft model of prostate cancer using human tumors. Nat. Protoc. 8, 836–848 (2013).

    CAS  Article  Google Scholar 

  58. 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).

    Article  Google Scholar 

  59. 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).

    CAS  Article  Google Scholar 

  60. 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).

    CAS  Article  Google Scholar 

  61. 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).

    CAS  Article  Google Scholar 

  62. 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).

    Article  Google Scholar 

  63. Efstathiou, E. et al. Morphologic characterization of preoperatively treated prostate cancer: toward a post-therapy histologic classification. Eur. Urol. 57, 1030–1038 (2010).

    Article  Google Scholar 

  64. Toivanen, R. et al. A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors. Sci. Transl Med. 5, 187ra171 (2013).

    Article  Google Scholar 

  65. 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).

    Article  Google Scholar 

  66. Bul, M. et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur. Urol. 63, 597–603 (2013).

    Article  Google Scholar 

  67. 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).

    Article  Google Scholar 

  68. 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).

    Article  PubMed  Google Scholar 

  69. Mateo, J. et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373, 1697–1708 (2015).

    CAS  Article  Google Scholar 

  70. 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).

    CAS  Article  Google Scholar 

  71. 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).

    CAS  Article  Google Scholar 

Download references

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

Authors

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

Correspondence to Gail P. Risbridger.

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-019-0164-8

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing