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.

Genomic and phenotypic heterogeneity in prostate cancer

Abstract

From a clinical, morphological and molecular perspective, prostate cancer is a heterogeneous disease. Primary prostate cancers are often multifocal, having topographically and morphologically distinct tumour foci. Sequencing studies have revealed that individual tumour foci can arise as clonally distinct lesions with no shared driver gene alterations. This finding demonstrates that multiple genomically and phenotypically distinct primary prostate cancers can be present in an individual patient. Lethal metastatic prostate cancer seems to arise from a single clone in the primary tumour but can exhibit subclonal heterogeneity at the genomic, epigenetic and phenotypic levels. Collectively, this complex heterogeneous constellation of molecular alterations poses obstacles for the diagnosis and treatment of prostate cancer. However, advances in our understanding of intra-tumoural heterogeneity and the development of novel technologies will allow us to navigate these challenges, refine approaches for translational research and ultimately improve patient care.

Key points

  • Primary prostate cancers are often multifocal with spatial and morphologically distinct tumour foci.

  • Individual tumour foci can show non-overlapping truncal genomic alterations, suggesting that multiple clonally distinct cancers can arise in a given patient.

  • Intra-tumoural and inter-tumoural heterogeneity present within the prostate gland poses diagnostic challenges.

  • Despite the multiclonality of primary cancer, clonal bottlenecks imposed by the metastatic process and further by therapeutic interventions seem to select for a single dominant clone in lethal metastatic prostate cancer.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Model of clonal progression of prostate cancer.
Fig. 2: Visualizing clonal and subclonal heterogeneity in tumour tissues.
Fig. 3: Multifocal prostate cancer.
Fig. 4: Morphological heterogeneity in mCRPC.
Fig. 5: Schematic of scenarios of clonal evolution of metastatic prostate cancer.

References

  1. Alizadeh, A. A. et al. Toward understanding and exploiting tumor heterogeneity. Nat. Med. 21, 846–853 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Marusyk, A., Almendro, V. & Polyak, K. Intra-tumour heterogeneity: a looking glass for cancer? Nat. Rev. Cancer 12, 323–334 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Gerlinger, M. et al. Intratumour heterogeneity in urologic cancers: from molecular evidence to clinical implications. Eur. Urol. 67, 729–737 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Mitchell, T. & Neal, D. E. The genomic evolution of human prostate cancer. Br. J. Cancer 113, 193–198 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251–256 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yap, T. A., Gerlinger, M., Futreal, P. A., Pusztai, L. & Swanton, C. Intratumor heterogeneity: seeing the wood for the trees. Sci. Transl Med. 4, 127ps10–127ps10 (2012).

    Article  PubMed  CAS  Google Scholar 

  9. Maley, C. C. et al. Classifying the evolutionary and ecological features of neoplasms. Nat. Rev. Cancer 17, 605–619 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).

    Article  PubMed  Google Scholar 

  11. Sartor, O. & de Bono, J. S. Metastatic prostate cancer. N. Engl. J. Med. 378, 645–657 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Nelson, W. G., De Marzo, A. M. & Isaacs, W. B. Prostate cancer. N. Engl. J. Med. 349, 366–381 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  14. Eschenbach, von,A. C. The biologic dilemma of early carcinoma of the prostate. Cancer 78, 326–329 (1996).

    Article  Google Scholar 

  15. Pound, C. R. et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281, 1591–1597 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Litwin, M. S. & Tan, H.-J. The diagnosis and treatment of prostate cancer: a review. JAMA 317, 2532–2542 (2017).

    Article  PubMed  Google Scholar 

  17. Aihara, M., Wheeler, T. M., Ohori, M. & Scardino, P. T. Heterogeneity of prostate cancer in radical prostatectomy specimens. Urology 43, 66–67 (1994).

    Article  Google Scholar 

  18. Cyll, K. et al. Tumour heterogeneity poses a significant challenge to cancer biomarker research. Br. J. Cancer 117, 367–375 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Andreoiu, M. & Cheng, L. Multifocal prostate cancer: biologic, prognostic, and therapeutic implications. Hum. Pathol. 41, 781–793 (2010).

    Article  PubMed  Google Scholar 

  20. Arora, R. et al. Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate. Cancer 100, 2362–2366 (2004).

    Article  PubMed  Google Scholar 

  21. Cheng, L. et al. Evidence of independent origin of multiple tumors from patients with prostate cancer. J. Natl. Cancer Inst. 90, 233–237 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Miller, G. J. & Cygan, J. M. Morphology of prostate cancer: the effects of multifocality on histological grade, tumor volume and capsule penetration. J. Urol. 152, 1709–1713 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Spratt, D. E., Zumsteg, Z. S., Feng, F. Y. & Tomlins, S. A. Translational and clinical implications of the genetic landscape of prostate cancer. Nat. Rev. Clin. Oncol. 13, 597–610 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor heterogeneity: the rosetta stone of therapy resistance. Cancer Cell 37, 471–484 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Boutros, P. C. et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat. Genet. 47, 736–745 (2015). Whole-genome sequencing of multiple tumour foci of five primary prostate cancer cases reveals independent tumour cell clones.

    Article  CAS  PubMed  Google Scholar 

  26. Fraser, M., Berlin, A., Bristow, R. G. & van der Kwast, T. Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer. Urol. Oncol. 33, 85–94 (2015).

    Article  PubMed  Google Scholar 

  27. Løvf, M. et al. Multifocal primary prostate cancer exhibits high degree of genomic heterogeneity. Eur. Urol. 75, 498–505 (2019). Detailed assessment of 41 cases shows that 76% of multifocal primary tumours are genomically distinct, providing strong evidence of the multiclonality of prostate cancer.

    Article  PubMed  CAS  Google Scholar 

  28. Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015). Seminal study demonstrating the complex clonal architecture of lethal metastatic prostate cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Haffner, M. C. et al. Tracking the clonal origin of lethal prostate cancer. J. Clin. Invest. 123, 4918–4922 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hong, M. K. H. et al. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat. Commun. 6, 6605–6612 (2015). Demonstrates the clonal dynamics and complex seeding pattern of advanced prostate cancer.

    Article  CAS  PubMed  Google Scholar 

  31. Beltran, H. et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22, 298–305 (2016). Comprehensive assessment of the clonal relationship of NEPC and the role of DNA methylation changes in lineage plasticity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lipinski, K. A. et al. Cancer evolution and the limits of predictability in precision cancer medicine. Trends Cancer 2, 49–63 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Espiritu, S. M. G. et al. The evolutionary landscape of localized prostate cancers drives clinical aggression. Cell 173, 1003–1013.e15 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Turajlic, S. & Swanton, C. Metastasis as an evolutionary process. Science 352, 169–175 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Turajlic, S. et al. Deterministic evolutionary trajectories influence primary tumor growth: TRACERx renal. Cell 173, 595–610.e11 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Reiter, J. G. et al. An analysis of genetic heterogeneity in untreated cancers. Nat. Rev. Cancer 19, 639–650 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tomasetti, C., Li, L. & Vogelstein, B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 355, 1330–1334 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Martincorena, I. & Campbell, P. J. Somatic mutation in cancer and normal cells. Science 349, 1483–1489 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Haffner, M. C. et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat. Genet. 42, 668–675 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Haffner, M. C., De Marzo, A. M., Meeker, A. K., Nelson, W. G. & Yegnasubramanian, S. Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target? Clin. Cancer Res. 17, 3858–3864 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019).

    Article  CAS  PubMed  Google Scholar 

  42. Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McGranahan, N. et al. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci. Transl Med. 7, 283ra54–283ra54 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Tomasetti, C., Vogelstein, B. & Parmigiani, G. Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. Proc. Natl Acad. Sci. USA 110, 1999–2004 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Moad, M. et al. Multipotent basal stem cells, maintained in localized proximal niches, support directed long-ranging epithelial flows in human prostates. CellReports 20, 1609–1622 (2017).

    CAS  Google Scholar 

  47. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Barber, L. J., Davies, M. N. & Gerlinger, M. Dissecting cancer evolution at the macro-heterogeneity and micro-heterogeneity scale. Curr. Opin. Genet. Dev. 30, 1–6 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. McPherson, A. et al. Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer. Nat. Genet. 48, 758–767 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Andor, N. et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat. Med. 22, 105–113 (2016).

    Article  CAS  PubMed  Google Scholar 

  54. Mroz, E. A. et al. High intratumor genetic heterogeneity is related to worse outcome in patients with head and neck squamous cell carcinoma. Cancer 119, 3034–3042 (2013).

    Article  PubMed  Google Scholar 

  55. Baca, S. C. et al. Punctuated evolutionof prostate cancer genomes. Cell 153, 666–677 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lindberg, J. et al. Exome sequencing of prostate cancer supports the hypothesis of independent tumour origins. Eur. Urol. 63, 347–353 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Van Etten, J. L. & Dehm, S. M. Clonal origin and spread of metastatic prostate cancer. Endocr. Relat. Cancer 23, R207–R217 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  59. De Marzo, A. M. et al. Inflammation in prostate carcinogenesis. Nat. Rev. Cancer 7, 256–269 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Tyekucheva, S. et al. Stromal and epithelial transcriptional map of initiation progression and metastatic potential of human prostate cancer. Nat. Commun. 8, 420 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Nonn, L., Ananthanarayanan, V. & Gann, P. H. Evidence for field cancerization of the prostate. Prostate 69, 1470–1479 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Mehra, R. et al. Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: molecular evidence for an independent group of diseases. Cancer Res. 67, 7991–7995 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Mehra, R. et al. Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Res. 68, 3584–3590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Han, B. et al. Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression. Mod. Pathol. 22, 1083–1093 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Park, K. et al. Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia 12, 590–598 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Furusato, B. et al. ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification. Prostate Cancer Prostatic Dis. 13, 228–237 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lu, Z. et al. Clonal evaluation of early onset prostate cancer by expression profiling of ERG, SPINK1, ETV1, and ETV4 on whole-mount radical prostatectomy tissue. Prostate 80, 38–50 (2020).

    Article  CAS  PubMed  Google Scholar 

  68. Jamaspishvili, T. et al. Clinical implications of PTEN loss in prostate cancer. Nat. Rev. Urol. 15, 222–234 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Guedes, L. B. et al. Analytic, preanalytic, and clinical validation of p53 IHC for detection of TP53 missense mutation in prostate cancer. Clin. Cancer Res. 23, 4693–4703 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tan, H.-L. et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin. Cancer Res. 20, 890–903 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Kobayashi, M. et al. Molecular analysis of multifocal prostate cancer by comparative genomic hybridization. Prostate 68, 1715–1724 (2008).

    Article  PubMed  Google Scholar 

  72. Bostwick, D. G. et al. Independent origin of multiple foci of prostatic intraepithelial neoplasia: comparison with matched foci of prostate carcinoma. Cancer 83, 1995–2002 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Cheng, L. et al. Allelic imbalance in the clonal evolution of prostate carcinoma. Cancer 85, 2017–2022 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Wu, B. et al. Intratumoral heterogeneity and genetic characteristics of prostate cancer. Int. J. Cancer 146, 3369–3378 (2020).

    Article  CAS  PubMed  Google Scholar 

  75. Boutros, P. C., Fraser, M., van der Kwast, T. & Bristow, R. G. Clonality of localized and metastatic prostate cancer. Curr. Opin. Urol. 26, 219–224 (2016).

    Article  PubMed  Google Scholar 

  76. VanderWeele, D. J. et al. Genomic heterogeneity within individual prostate cancer foci impacts predictive biomarkers of targeted therapy. Eur. Urol. Focus. 5, 416–424 (2019).

    Article  PubMed  Google Scholar 

  77. Macintyre, G. et al. How subclonal modeling is changing the metastatic paradigm. Clin. Cancer Res. 23, 630–635 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Mitchell, T. J. et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell 173, 611–623.e17 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gerstung, M. et al. The evolutionary history of 2,658 cancers. Nature 578, 122–128 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Baslan, T. & Hicks, J. Unravelling biology and shifting paradigms in cancer with single-cell sequencing. Nat. Rev. Cancer 17, 557–569 (2017).

    Article  CAS  PubMed  Google Scholar 

  81. Alexander, J. et al. Utility of single-cell genomics in diagnostic evaluation of prostate cancer. Cancer Res. 78, 348–358 (2018).

    Article  CAS  PubMed  Google Scholar 

  82. Su, F. et al. Spatial intratumor genomic heterogeneity within localized prostate cancer revealed by single-nucleus sequencing. Eur. Urol. 74, 551–559 (2018).

    Article  PubMed  Google Scholar 

  83. Wang, Y. et al. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 512, 155–160 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kim, C. et al. Chemoresistance evolution in triple-negative breast cancer delineated by single-cell sequencing. Cell 173, 879–893.e13 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Grosselin, K. et al. High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer. Nat. Genet. 51, 1060–1066 (2019).

    Article  CAS  PubMed  Google Scholar 

  86. Li, G. et al. Joint profiling of DNA methylation and chromatin architecture in single cells. Nat. Methods 16, 991–993 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Berglund, E. et al. Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity. Nat. Commun. 9, 2419 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Decalf, J., Albert, M. L. & Ziai, J. New tools for pathology: a user’s review of a highly multiplexed method for in situ analysis of protein and RNA expression in tissue. J. Pathol. 247, 650–661 (2019).

    Article  PubMed  Google Scholar 

  89. Latonen, L. et al. Integrative proteomics in prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression. Nat. Commun. 9, 1176 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Sinha, A. et al. The proteogenomic landscape of curable prostate cancer. Cancer Cell 35, 414–427.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhu, Y. et al. High-throughput proteomic analysis of FFPE tissue samples facilitates tumor stratification. Mol. Oncol. 13, 2305–2328 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Charmpi, K. et al. Proteogenomic heterogeneity of localized human prostate cancer progression. Preprint at bioRxiv https://doi.org/10.1101/2020.02.16.950378 (2020).

    Article  Google Scholar 

  93. McNeal, J. E. The zonal anatomy of the prostate. Prostate 2, 35–49 (1981).

    Article  CAS  PubMed  Google Scholar 

  94. McNeal, J. E., Redwine, E. A., Freiha, F. S. & Stamey, T. A. Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread. Am. J. Surg. Pathol. 12, 897–906 (1988).

    Article  CAS  PubMed  Google Scholar 

  95. Shaikhibrahim, Z. et al. Genes differentially expressed in the peripheral zone compared to the transitional zone of the normal human prostate and their potential regulation by ETS factors. Mol. Med. Rep. 5, 32–36 (2012).

    CAS  Google Scholar 

  96. Guo, C. C., Zuo, G., Cao, D., Troncoso, P. & Czerniak, B. A. Prostate cancer of transition zone origin lacks TMPRSS2-ERG gene fusion. Mod. Pathol. 22, 866–871 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Sundi, D. et al. Pathological examination of radical prostatectomy specimens in men with very low risk disease at biopsy reveals distinct zonal distribution of cancer in black American men. J. Urol. 191, 60–67 (2014).

    Article  PubMed  Google Scholar 

  98. Epstein, J. I. Prostate cancer grading: a decade after the 2005 modified system. Mod. Pathol. 31, S47–S63 (2018).

    Article  PubMed  Google Scholar 

  99. Elfandy, H. et al. Genetic and epigenetic determinants of aggressiveness in cribriform carcinoma of the prostate. Mol. Cancer Res. 17, 446–456 (2019).

    Article  CAS  PubMed  Google Scholar 

  100. Hollemans, E. et al. Large cribriform growth pattern identifies ISUP grade 2 prostate cancer at high risk for recurrence and metastasis. Mod. Pathol. 32, 139–146 (2019).

    Article  CAS  PubMed  Google Scholar 

  101. Schweizer, M. T. et al. Genomic characterization of prostatic ductal adenocarcinoma identifies a high prevalence of DNA repair gene mutations. JCO Precis. Oncol. 3, 1–9 (2019).

    Google Scholar 

  102. Rubin, M. A., Girelli, G. & Demichelis, F. Genomic correlates to the newly proposed grading prognostic groups for prostate cancer. Eur. Urol. 69, 557–560 (2016).

    Article  PubMed  Google Scholar 

  103. Lotan, T. L. et al. PTEN loss as determined by clinical-grade immunohistochemistry assay is associated with worse recurrence-free survival in prostate cancer. Eur. Urol. Focus. 2, 180–188 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Kovtun, I. V. et al. Lineage relationship of Gleason patterns in Gleason score 7 prostate cancer. Cancer Res. 73, 3275–3284 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Sowalsky, A. G., Ye, H., Bubley, G. J. & Balk, S. P. Clonal progression of prostate cancers from Gleason grade 3 to grade 4. Cancer Res. 73, 1050–1055 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Sowalsky, A. G. et al. Gleason score 7 prostate cancers emerge through branched evolution of clonal Gleason pattern 3 and 4. Clin. Cancer Res. 23, 3823–3833 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ye, H. & Sowalsky, A. G. Molecular correlates of intermediate- and high-risk localized prostate cancer. Urol. Oncol. 36, 368–374 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. VanderWeele, D. J. et al. Low-grade prostate cancer diverges early from high grade and metastatic disease. Cancer Sci. 105, 1079–1085 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Karavitakis, M., Ahmed, H. U., Abel, P. D., Hazell, S. & Winkler, M. H. Tumor focality in prostate cancer: implications for focal therapy. Nat. Rev. Clin. Oncol. 8, 48–55 (2011).

    Article  PubMed  Google Scholar 

  110. Humphrey, P. A. Complete histologic serial sectioning of a prostate gland with adenocarcinoma. Am. J. Surg. Pathol. 17, 468–472 (1993).

    Article  CAS  PubMed  Google Scholar 

  111. van Royen, M. E. et al. Three-dimensional microscopic analysis of clinical prostate specimens. Histopathology 69, 985–992 (2016).

    Article  PubMed  Google Scholar 

  112. Barry, M., Perner, S., Demichelis, F. & Rubin, M. A. TMPRSS2-ERG fusion heterogeneity in multifocal prostate cancer: clinical and biologic implications. Urology 70, 630–633 (2007).

    Article  PubMed  Google Scholar 

  113. Ruijter, E. T. et al. Molecular analysis of multifocal prostate cancer lesions. J. Pathol. 188, 271–277 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Aryee, M. J. et al. DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. Sci. Transl Med. 5, 169ra10–169ra10 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Mundbjerg, K. et al. Identifying aggressive prostate cancer foci using a DNA methylation classifier. Genome Biol. 18, 3–15 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Brocks, D. et al. Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. CellReports 8, 798–806 (2014).

    CAS  Google Scholar 

  117. Stelloo, S. et al. Integrative epigenetic taxonomy of primary prostate cancer. Nat. Commun. 9, 4900–4912 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Fontugne, J. et al. Clonal evaluation of prostate cancer foci in biopsies with discontinuous tumor involvement by dual ERG/SPINK1 immunohistochemistry. Mod. Pathol. 29, 157–165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kristiansen, A. et al. Somatic alterations detected in diagnostic prostate biopsies provide an inadequate representation of multifocal prostate cancer. Prostate 79, 920–928 (2019).

    Article  CAS  PubMed  Google Scholar 

  120. Brastianos, P. K. et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 5, 1164–1177 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Haffner, M. C., De Marzo, A. M., Yegnasubramanian, S., Epstein, J. I. & Carter, H. B. Diagnostic challenges of clonal heterogeneity in prostate cancer. J. Clin. Oncol. 33, e38–e40 (2015).

    Article  PubMed  Google Scholar 

  122. Stabile, A. et al. Multiparametric MRI for prostate cancer diagnosis: current status and future directions. Nat. Rev. Urol. 17, 41–61 (2020).

    Article  PubMed  Google Scholar 

  123. Valerio, M. et al. Detection of clinically significant prostate cancer using magnetic resonance imaging-ultrasound fusion targeted biopsy: a systematic review. Eur. Urol. 68, 8–19 (2015).

    Article  PubMed  Google Scholar 

  124. Sathianathen, N. J. et al. Accuracy of the magnetic resonance imaging pathway in the detection of prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 22, 39–48 (2019).

    Article  PubMed  Google Scholar 

  125. Harmon, S. A., Tuncer, S., Sanford, T., Choyke, P. L. & Türkbey, B. Artificial intelligence at the intersection of pathology and radiology in prostate cancer. Diagn. Interv. Radiol. 25, 183–188 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Houlahan, K. E. et al. Molecular hallmarks of multiparametric magnetic resonance imaging visibility in prostate cancer. Eur. Urol. 76, 18–23 (2019).

    Article  CAS  PubMed  Google Scholar 

  127. Cucchiara, V. et al. Genomic markers in prostate cancer decision making. Eur. Urol. 73, 572–582 (2018).

    Article  PubMed  Google Scholar 

  128. Loeb, S. & Ross, A. E. Genomic testing for localized prostate cancer: where do we go from here? Curr. Opin. Urol. 27, 495–499 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wei, L. et al. Intratumoral and intertumoral genomic heterogeneity of multifocal localized prostate cancer impacts molecular classifications and genomic prognosticators. Eur. Urol. 71, 183–192 (2017).

    Article  CAS  PubMed  Google Scholar 

  130. Salami, S. S. et al. Transcriptomic heterogeneity in multifocal prostate cancer. JCI Insight 3, 3 (2018).

    Article  Google Scholar 

  131. Sowalsky, A. G. et al. Neoadjuvant-intensive androgen deprivation therapy selects for prostate tumor foci with diverse subclonal oncogenic alterations. Cancer Res. 78, 4716–4730 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wilkinson, S. et al. A case report of multiple primary prostate tumors with differential drug sensitivity. Nat. Commun. 11, 837–838 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kneppers, J. et al. Frequent clonal relations between metastases and non-index prostate cancer lesions. JCI Insight 4, e124756 (2019).

    Article  PubMed Central  Google Scholar 

  134. Epstein, J. I., Amin, M. B., Reuter, V. E. & Humphrey, P. A. Contemporary Gleason grading of prostatic carcinoma: an update with discussion on practical issues to implement the 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am. J. Surg. Pathol. 41, e1–e7 (2017).

    Article  PubMed  Google Scholar 

  135. Valerio, M. et al. New and established technology in focal ablation of the prostate: a systematic review. Eur. Urol. 71, 17–34 (2017).

    Article  PubMed  Google Scholar 

  136. Ross, H. M. et al. Do adenocarcinomas of the prostate with Gleason score (GS) ≤6 have the potential to metastasize to lymph nodes? Am. J. Surg. Pathol. 36, 1346–1352 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Trock, B. J. et al. PTEN loss and chromosome 8 alterations in Gleason grade 3 prostate cancer scores predicts the presence of un-sampled grade 4 tumor: implications for active surveillance. Mod. Pathol. 29, 764–771 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lotan, T. L. et al. PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod. Pathol. 28, 128–137 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Moschini, M. et al. Natural history of clinical recurrence patterns of lymph node-positive prostate cancer after radical prostatectomy. Eur. Urol. 69, 135–142 (2016).

    Article  PubMed  Google Scholar 

  140. Touijer, K. A., Mazzola, C. R., Sjoberg, D. D., Scardino, P. T. & Eastham, J. A. Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Eur. Urol. 65, 20–25 (2014).

    Article  PubMed  Google Scholar 

  141. Chaffer, C. L. & Weinberg, R. A. A perspective on cancer cell metastasis. Science 331, 1559–1564 (2011).

    Article  CAS  PubMed  Google Scholar 

  142. Naxerova, K. et al. Origins of lymphatic and distant metastases in human colorectal cancer. Science 357, 55–60 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Mangiola, S. et al. Comparing nodal versus bony metastatic spread using tumour phylogenies. Sci. Rep. 6, 33918 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Pienta, K. J., Robertson, B. A., Coffey, D. S. & Taichman, R. S. The cancer diaspora: metastasis beyond the seed and soil hypothesis. Clin. Cancer Res. 19, 5849–5855 (2013).

    Article  PubMed  Google Scholar 

  145. van der Toom, E. E., Verdone, J. E. & Pienta, K. J. Disseminated tumor cells and dormancy in prostate cancer metastasis. Curr. Opin. Biotechnol. 40, 9–15 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Massagué, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Antonarakis, E. S. et al. The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up. BJU Int. 109, 32–39 (2012).

    Article  CAS  PubMed  Google Scholar 

  148. Priestley, P. et al. Pan-cancer whole-genome analyses of metastatic solid tumours. Nature 575, 210–216 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Reiter, J. G. et al. Minimal functional driver gene heterogeneity among untreated metastases. Science 361, 1033–1037 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Marusyk, A. et al. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 514, 54–58 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Merlo, L. M. F., Pepper, J. W., Reid, B. J. & Maley, C. C. Cancer as an evolutionary and ecological process. Nat. Rev. Cancer 6, 924–935 (2006).

    Article  CAS  PubMed  Google Scholar 

  152. Landau, D. A. et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152, 714–726 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Watson, P. A., Arora, V. K. & Sawyers, C. L. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer 15, 701–711 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Bluemn, E. G. et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell 32, 474–489.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Polkinghorn, W. R. et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 3, 1245–1253 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Goodwin, J. F. et al. A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov. 3, 1254–1271 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. Sweeney, C. J. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N. Engl. J. Med. 373, 737–746 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Roudier, M. P. et al. Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. Hum. Pathol. 34, 646–653 (2003).

    Article  PubMed  Google Scholar 

  160. Shah, R. B. et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 64, 9209–9216 (2004).

    Article  CAS  PubMed  Google Scholar 

  161. Aggarwal, R. et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J. Clin. Oncol. 36, 2492–2503 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Epstein, J. I. et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am. J. Surg. Pathol. 38, 756–767 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Labrecque, M. P. et al. Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. J. Clin. Invest. 130, 4492–4505 (2019). Definition of molecular subclasses of metastatic prostate cancers by comprehensive expression analyses.

    Article  Google Scholar 

  164. Beltran, H. et al. The role of lineage plasticity in prostate cancer therapy resistance. Clin. Cancer Res. 25, 6916–6924 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Nadal, R., Schweizer, M., Kryvenko, O. N., Epstein, J. I. & Eisenberger, M. A. Small cell carcinoma of the prostate. Nat. Rev. Urol. 11, 213–219 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Quintanal-Villalonga, Á. et al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat. Rev. Clin. Oncol. 20, 2429 (2020).

    Google Scholar 

  167. Beltran, H. et al. Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer. J. Clin. Invest. 130, 1653–1668 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Beltran, H. & Demichelis, F. Prostate cancer: intrapatient heterogeneity in prostate cancer. Nat. Rev. Urol. 12, 430–431 (2015).

    Article  PubMed  Google Scholar 

  169. Stapleton, A. M. et al. Primary human prostate cancer cells harboring p53 mutations are clonally expanded in metastases. Clin. Cancer Res. 3, 1389–1397 (1997).

    CAS  PubMed  Google Scholar 

  170. Chesire, D. R., Ewing, C. M., Sauvageot, J., Bova, G. S. & Isaacs, W. B. Detection and analysis of beta-catenin mutations in prostate cancer. Prostate 45, 323–334 (2000).

    Article  CAS  PubMed  Google Scholar 

  171. Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kumar, A. et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat. Med. 22, 369–378 (2016). Assessment of genomic and transcriptomic heterogeneity in mCRPC reveals shared driver alterations and highly similar expression pattern in anatomically distinct metastases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Liu, W. et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat. Med. 15, 559–565 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Heidenreich, A. et al. Cytoreductive radical prostatectomy in men with prostate cancer and skeletal metastases. Eur. Urol. Oncol. 1, 46–53 (2018).

    Article  PubMed  Google Scholar 

  175. Phillips, R. et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 6, 650–659 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Wu, A. et al. Genome-wide plasma DNA methylation features of metastatic prostate cancer. J. Clin. Invest. 130, 1991–2000 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Mateo, J. et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J. Clin. Invest. 130, 1743–1751 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Quigley, D. A. et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell 174, 758–769.e9 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. van Dessel, L. F. et al. The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact. Nat. Commun. 10, 5251 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Lambros, M. B. et al. Single-cell analyses of prostate cancer liquid biopsies acquired by apheresis. Clin. Cancer Res. 24, 5635–5644 (2018).

    Article  CAS  PubMed  Google Scholar 

  181. Hussain, M. et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 378, 2465–2474 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Stelloo, S., Bergman, A. M. & Zwart, W. Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers. Endocr. Relat. Cancer 26, R267–R285 (2019).

    Article  CAS  PubMed  Google Scholar 

  183. Yegnasubramanian, S., De Marzo, A. M. & Nelson, W. G. Prostate cancer epigenetics: from basic mechanisms to clinical implications. Cold Spring Harb. Perspect. Med. 9, a030445 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Feinberg, A. P. Phenotypic plasticity and the epigenetics of human disease. Nature 447, 433–440 (2007).

    Article  CAS  PubMed  Google Scholar 

  185. Drake, J. M. et al. Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets. Proc. Natl Acad. Sci. USA 110, E4762–E4769 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Nava Rodrigues, D. et al. RB1 heterogeneity in advanced metastatic castration-resistant prostate cancer. Clin. Cancer Res. 25, 687–697 (2019).

    Article  PubMed  Google Scholar 

  187. Li, Q. et al. Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat. Commun. 9, 3600–3617 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Carreira, S. et al. Tumor clone dynamics in lethal prostate cancer. Sci. Transl Med. 6, 254ra125 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Romanel, A. et al. Plasma AR and abiraterone-resistant prostate cancer. Sci. Transl Med. 7, 312re10 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Diaz, L. A. et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486, 537–540 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Abida, W. et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc. Natl Acad. Sci. USA 116, 11428–11436 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Quigley, D. et al. Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. Cancer Discov. 7, 999–1005 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Wu, A. & Attard, G. Plasma DNA analysis in prostate cancer: opportunities for improving clinical management. Clin. Chem. 65, 100–107 (2019).

    Article  CAS  PubMed  Google Scholar 

  195. Mahon, K. L. et al. Methylated glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer. Br. J. Cancer 111, 1802–1809 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Antonarakis, E. S. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 371, 1028–1038 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Morin, F. et al. Metabolic imaging of prostate cancer reveals intrapatient intermetastasis response heterogeneity to systemic therapy. Eur. Urol. Focus. 3, 639–642 (2017).

    Article  PubMed  Google Scholar 

  198. Fox, J. J. et al. Positron emission tomography/computed tomography-based assessments of androgen receptor expression and glycolytic activity as a prognostic biomarker for metastatic castration-resistant prostate cancer. JAMA Oncol. 4, 217–224 (2018).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank C. Morrissey (University of Washington), T. Lotan (Johns Hopkins School of Medicine) and W. B. Isaacs (Johns Hopkins School of Medicine), as well as members of the Haffner, Yegnasubramanian and Nelson laboratories, for valuable discussions and suggestions on the manuscript. This work of the authors is supported by the NIH/NCI (P50CA097186, P50CA58236, U01 CA196390, P30 CA006973, R01CA183965), the US Department of Defense Prostate Cancer Research Program (W81XWH-20-1-0111, W81XWH-18-1-0406, W81XWH-18-2-0015), the Prostate Cancer Foundation, the Safeway Foundation, the Commonwealth Foundation and the Irving Hansen Memorial Foundation.

Author information

Authors and Affiliations

Authors

Contributions

M.C.H., J.I.E., P.S.N. and S.Y. researched data for the article, made a substantial contribution to discussion of content, wrote and reviewed/edited the manuscript before submission. W.Z. and M.P.R. researched data for the article, made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission. L.D.T. reviewed/edited the manuscript before submission. W.G.N. made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission. A.M.D.M. made a substantial contribution to discussion of content, wrote and reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Michael C. Haffner.

Ethics declarations

Competing interests

S.Y., W.G.N. and A.M.D.M. are paid consultants to and received sponsored research funding from Cepheid. S.Y. and W.G.N. are co-inventors of intellectual property describing the use of DNA methylation changes as prostate cancer biomarkers and are eligible to earn royalties related to the future sale of any products using those technologies. S.Y. and A.M.D.M. receive sponsored research funding from Janssen. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Urology thanks Mark Rubin, Kent Mouw and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Inter-patient heterogeneity

Differences in tumour genotypes and phenotypes between individual patients.

Intra-tumoural heterogeneity

Genomic, epigenetic, transcriptomic and phenotypic differences within a tumour mass.

Inter-tumoural heterogeneity

Differences between anatomically distinct tumour sites within a given patient.

Multifocality

Spatially distinct and often histomorphologically different tumour lesions within one affected organ.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haffner, M.C., Zwart, W., Roudier, M.P. et al. Genomic and phenotypic heterogeneity in prostate cancer. Nat Rev Urol 18, 79–92 (2021). https://doi.org/10.1038/s41585-020-00400-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-020-00400-w

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer