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.

  • Review Article
  • Published:

Clinical implications of PTEN loss in prostate cancer

Nature Reviews Urology volume 15, pages 222–234 (2018)Cite this article

Subjects

Key Points

  • Large-scale next-generation genetic analyses of prostate cancer emphasize the frequent occurrence and importance of focal genomic deletions inactivating PTEN

  • Phosphatase and tensin homologue (PTEN) loss in radical prostatectomy samples is often concurrent with genomic rearrangements involving the ETS family transcription factors

  • PTEN loss is reproducibly associated with adverse oncological outcomes by itself or in combination with other biomarkers and helps distinguish indolent tumours from those likely to progress

  • PTEN might be a useful prognostic biomarker to distinguish potentially aggressive Grade Group 1 or 2 tumours, which might make patients poor candidates for active surveillance programmes

  • Robust clinical assays using immunohistochemistry and fluorescence in situ hybridization (FISH) have been developed to reproducibly measure PTEN protein and gene loss using diagnostic tissue biopsies and circulating tumour cells from plasma

  • PTEN loss is associated with suppression of androgen receptor (AR) transcriptional output, and phosphoinositide 3-kinase (PI3K) inhibitors activate AR signalling, suggesting potential efficacy of combination therapies targeting the PI3K and AR signalling pathways

  • Emerging studies indicate that PTEN loss is associated with alterations to cellular interferon responses in the tumour microenvironment — tumours with loss of PTEN are more likely to have an immunosuppressive microenvironment, suggesting that advanced prostate cancers with PTEN loss might be amenable to immune-based therapies

Abstract

Genomic aberrations of the PTEN tumour suppressor gene are among the most common in prostate cancer. Inactivation of PTEN by deletion or mutation is identified in ∼20% of primary prostate tumour samples at radical prostatectomy and in as many as 50% of castration-resistant tumours. Loss of phosphatase and tensin homologue (PTEN) function leads to activation of the PI3K–AKT (phosphoinositide 3-kinase–RAC-alpha serine/threonine-protein kinase) pathway and is strongly associated with adverse oncological outcomes, making PTEN a potentially useful genomic marker to distinguish indolent from aggressive disease in patients with clinically localized tumours. At the other end of the disease spectrum, therapeutic compounds targeting nodes in the PI3K–AKT–mTOR (mechanistic target of rapamycin) signalling pathway are being tested in clinical trials for patients with metastatic castration-resistant prostate cancer. Knowledge of PTEN status might be helpful to identify patients who are more likely to benefit from these therapies. To enable the use of PTEN status as a prognostic and predictive biomarker, analytically validated assays have been developed for reliable and reproducible detection of PTEN loss in tumour tissue and in blood liquid biopsies. The use of clinical-grade assays in tumour tissue has shown a robust correlation between loss of PTEN and its protein as well as a strong association between PTEN loss and adverse pathological features and oncological outcomes. In advanced disease, assessing PTEN status in liquid biopsies shows promise in predicting response to targeted therapy. Finally, studies have shown that PTEN might have additional functions that are independent of the PI3K–AKT pathway, including those affecting tumour growth through modulation of the immune response and tumour microenvironment.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The diverse cellular roles of PTEN.
Figure 2: Prostate cancer samples with variable PTEN protein expression by IHC and corresponding PTEN FISH.
Figure 3: Heterogeneous immunohistochemical expression of ERG and PTEN in prostate tumours.
Figure 4: Algorithm for when to determine PTEN status on diagnostic biopsy material using IHC and FISH.
Figure 5: Proposed management options using clinicopathological variables at biopsy and PTEN status.
Figure 6: Selected drugs in clinical trials targeting the PI3K–AKT pathway that have been used in combination with androgen deprivation therapy.

Similar content being viewed by others

References

  1. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2017. CA Cancer J. Clin. 67, 7–30 (2017).

    Article  PubMed  Google Scholar 

  2. Tosoian, J. J. et al. Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. J. Clin. Oncol. 33, 3379–3385 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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

  4. Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Maehama, T. & Dixon, J. E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273, 13375–13378 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nat. Rev. Mol. Cell Biol. 13, 283–296 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Li, S. et al. The tumor suppressor PTEN has a critical role in antiviral innate immunity. Nat. Immunol. 17, 241–249 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Chen, L. & Guo, D. The functions of tumor suppressor PTEN in innate and adaptive immunity. Cell. Mol. Immunol. 14, 581–589 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tamura, M. et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280, 1614–1617 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Zhang, S. et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat. Med. 17, 461–469 (2011).

    Article  PubMed  CAS  Google Scholar 

  11. Weng, L. P., Brown, J. L. & Eng, C. PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Hum. Mol. Genet. 10, 599–604 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Lindsay, Y. et al. Localization of agonist-sensitive PtdIns(3,4,5)P3 reveals a nuclear pool that is insensitive to PTEN expression. J. Cell Sci. 119, 5160–5168 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Shen, W. H. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Bassi, C. et al. Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress. Science 341, 395–399 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cairns, P. et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 57, 4997–5000 (1997).

    CAS  PubMed  Google Scholar 

  16. Steck, P. A. et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet. 15, 356–362 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Suzuki, H. et al. Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res. 58, 204–209 (1998).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yoshimoto, M. et al. FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome. Br. J. Cancer 97, 678–685 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Krohn, A. et al. Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. Am. J. Pathol. 181, 401–412 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Troyer, D. A. et al. A multicenter study shows PTEN deletion is strongly associated with seminal vesicle involvement and extracapsular extension in localized prostate cancer. Prostate 75, 1206–1215 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Feilotter, H. E., Nagai, M. A., Boag, A. H., Eng, C. & Mulligan, L. M. Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene 16, 1743–1748 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Pesche, S. et al. PTEN/MMAC1/TEP1 involvement in primary prostate cancers. Oncogene 16, 2879–2883 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Wang, S. I., Parsons, R. & Ittmann, M. Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas. Clin. Cancer Res. 4, 811–815 (1998).

    CAS  PubMed  Google Scholar 

  26. Whang, Y. E. et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc. Natl Acad. Sci. USA 95, 5246–5250 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yoshimoto, M. et al. Interphase FISH analysis of PTEN in histologic sections shows genomic deletions in 68% of primary prostate cancer and 23% of high-grade prostatic intra-epithelial neoplasias. Cancer Genet. Cytogenet. 169, 128–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Verhagen, P. C. et al. The PTEN gene in locally progressive prostate cancer is preferentially inactivated by bi-allelic gene deletion. J. Pathol. 208, 699–707 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. McCall, P., Witton, C. J., Grimsley, S., Nielsen, K. V. & Edwards, J. Is PTEN loss associated with clinical outcome measures in human prostate cancer? Br. J. Cancer 99, 1296–1301 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yoshimoto, M. et al. Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Mod. Pathol. 21, 1451–1460 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Attard, G. et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 69, 2912–2918 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Sircar, K. et al. PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer. J. Pathol. 218, 505–513 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. Krohn, A. et al. Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer. Mod. Pathol. 27, 1612–1620 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Steurer, S. et al. TMPRSS2-ERG fusions are strongly linked to young patient age in low-grade prostate cancer. Eur. Urol. 66, 978–981 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Lotan, T. L. et al. Analytic validation of a clinical-grade PTEN immunohistochemistry assay in prostate cancer by comparison with PTEN FISH. Mod. Pathol. 29, 904–914 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ahearn, T. U. et al. A prospective investigation of PTEN loss and ERG expression in lethal prostate cancer. J. Natl Cancer Inst. 108, djv34 (2016).

    Google Scholar 

  38. 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 

  39. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Khani, F. et al. Evidence for molecular differences in prostate cancer between African American and Caucasian men. Clin. Cancer Res. 20, 4925–4934 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tosoian, J. J. et al. Prevalence and prognostic significance of PTEN loss in African-American and European-American men undergoing radical prostatectomy. Eur. Urol. 71, 697–700 (2017).

    Article  PubMed  Google Scholar 

  43. Lindquist, K. J. et al. Mutational landscape of aggressive prostate tumors in African American men. Cancer Res. 76, 1860–1868 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Huang, F. W. et al. Exome sequencing of African-American prostate cancer reveals loss-of-function ERF mutations. Cancer Discov. 7, 973–983 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Reid, A. H. et al. Novel, gross chromosomal alterations involving PTEN cooperate with allelic loss in prostate cancer. Mod. Pathol. 25, 902–910 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Murphy, S. J. et al. Integrated analysis of the genomic instability of PTEN in clinically insignificant and significant prostate cancer. Mod. Pathol. 29, 143–156 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Ibeawuchi, C. et al. Exploring prostate cancer genome reveals simultaneous losses of PTEN, FAS and PAPSS2 in patients with PSA recurrence after radical prostatectomy. Int. J. Mol. Sci. 16, 3856–3869 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Whang, Y. E., Wu, X. Y. & Sawyers, C. L. Identification of a pseudogene that can masquerade as a mutant allele of the PTEN/MMAC1 tumor suppressor gene. J. Natl Cancer Inst. 90, 859–861 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Zysman, M. A., Chapman, W. B. & Bapat, B. Considerations when analyzing the methylation status of PTEN tumor suppressor gene. Am. J. Pathol. 160, 795–800 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Beltran, H. et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur. Urol. 63, 920–926 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Bermudez Brito, M., Goulielmaki, E. & Papakonstanti, E. A. Focus on PTEN Regulation. Front. Oncol. 5, 166 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Garcia, J. M. et al. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer 41, 117–124 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Konishi, N. et al. Heterogeneous methylation and deletion patterns of the INK4a/ARF locus within prostate carcinomas. Am. J. Pathol. 160, 1207–1214 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tay, Y. et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147, 344–357 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Poliseno, L. et al. Identification of the miR-106b∼25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci. Signal. 3, ra29 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Leslie, N. R. & Foti, M. Non-genomic loss of PTEN function in cancer: not in my genes. Trends Pharmacol. Sci. 32, 131–140 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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 

  60. Bismar, T. A. et al. PTEN genomic deletion is an early event associated with ERG gene rearrangements in prostate cancer. BJU Int. 107, 477–485 (2011).

    Article  PubMed  Google Scholar 

  61. Gumuskaya, B. et al. Assessing the order of critical alterations in prostate cancer development and progression by IHC: further evidence that PTEN loss occurs subsequent to ERG gene fusion. Prostate Cancer Prostat. Dis. 16, 209–215 (2013).

    Article  CAS  Google Scholar 

  62. 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 

  63. Lotan, T. L. et al. Cytoplasmic PTEN protein loss distinguishes intraductal carcinoma of the prostate from high-grade prostatic intraepithelial neoplasia. Mod. Pathol. 26, 587–603 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Morais, C. L. et al. Utility of PTEN and ERG immunostaining for distinguishing high-grade PIN from intraductal carcinoma of the prostate on needle biopsy. Am. J. Surg. Pathol. 39, 169–178 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Morais, C. L. et al. ERG and PTEN status of isolated high-grade PIN occurring in cystoprostatectomy specimens without invasive prostatic adenocarcinoma. Hum. Pathol. 55, 117–125 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Trotman, L. C. et al. Pten dose dictates cancer progression in the prostate. PLOS Biol. 1, E59 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P. P. Pten is essential for embryonic development and tumour suppression. Nat. Genet. 19, 348–355 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. Stambolic, V. et al. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/− mice. Cancer Res. 60, 3605–3611 (2000).

    CAS  PubMed  Google Scholar 

  69. Podsypanina, K. et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl Acad. Sci. USA 96, 1563–1568 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, S. et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209–221 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Shen, M. M. & Abate-Shen, C. Pten inactivation and the emergence of androgen-independent prostate cancer. Cancer Res. 67, 6535–6538 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Jiao, J. et al. Murine cell lines derived from Pten null prostate cancer show the critical role of PTEN in hormone refractory prostate cancer development. Cancer Res. 67, 6083–6091 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Mulholland, D. J. et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 19, 792–804 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Carver, B. S. et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Choucair, K. et al. PTEN genomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity. BMC Cancer 12, 543 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bismar, T. A. et al. Interactions and relationships of PTEN, ERG, SPINK1 and AR in castration-resistant prostate cancer. Histopathology 60, 645–652 (2012).

    Article  PubMed  Google Scholar 

  78. Grabowska, M. M. et al. Mouse models of prostate cancer: picking the best model for the question. Cancer Metastasis Rev. 33, 377–397 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Carver, B. S. et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat. Genet. 41, 619–624 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. King, J. C. et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat. Genet. 41, 524–526 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chen, Y. et al. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat. Med. 19, 1023–1029 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kim, J. et al. A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53. Oncogene 31, 322–332 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Couto, S. S. et al. Simultaneous haploinsufficiency of Pten and Trp53 tumor suppressor genes accelerates tumorigenesis in a mouse model of prostate cancer. Differentiation 77, 103–111 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 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 

  86. Aparicio, A. M. et al. Combined tumor suppressor defects characterize clinically defined aggressive variant prostate cancers. Clin. Cancer Res. 22, 1520–1530 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Hubbard, G. K. et al. Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Cancer Res. 76, 283–292 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Blattner, M. et al. SPOP mutation drives prostate tumorigenesis in vivo through coordinate regulation of PI3K/mTOR and AR signaling. Cancer Cell 31, 436–451 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zhao, D. et al. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature 542, 484–488 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Moschini, M. et al. Low-risk prostate cancer: identification, management, and outcomes. Eur. Urol. 72, 238–249 (2017).

    Article  PubMed  Google Scholar 

  91. Bruinsma, S. M. et al. Active surveillance for prostate cancer: a narrative review of clinical guidelines. Nat. Rev. Urol. 13, 151–167 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Barrett, T. & Haider, M. A. The emerging role of MRI in prostate cancer active surveillance and ongoing challenges. AJR Am. J. Roentgenol. 208, 131–139 (2017).

    Article  PubMed  Google Scholar 

  93. Ma, T. M. et al. The role of multiparametric magnetic resonance imaging/ultrasound fusion biopsy in active surveillance. Eur. Urol. 71, 174–180 (2017).

    Article  PubMed  Google Scholar 

  94. Epstein, J. I. et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: definition of grading patterns and proposal for a new grading system. Am. J. Surg. Pathol. 40, 244–252 (2016).

    Article  PubMed  Google Scholar 

  95. 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  PubMed  Google Scholar 

  96. Ross, A. E., D'Amico, A. V. & Freedland, S. J. Which, when and why? Rational use of tissue-based molecular testing in localized prostate cancer. Prostate Cancer Prostat. Dis. 19, 1–6 (2016).

    Article  CAS  Google Scholar 

  97. Lotan, T. L. et al. PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin. Cancer Res. 17, 6563–6573 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wang, Y. & Dai, B. PTEN genomic deletion defines favorable prognostic biomarkers in localized prostate cancer: a systematic review and meta-analysis. Int. J. Clin. Exp. Med. 8, 5430–5437 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Reid, A. H. et al. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br. J. Cancer 102, 678–684 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Trock, B. J. et al. PTEN loss and chromosome 8 alterations in Gleason grade 3 prostate cancer cores 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 

  101. Lotan, T. L. et al. PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod. Pathol. 28, 128–137 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Picanco-Albuquerque, C. G. et al. In prostate cancer needle biopsies, detections of PTEN loss by fluorescence in situ hybridization (FISH) and by immunohistochemistry (IHC) are concordant and show consistent association with upgrading. Virchows Arch. 468, 607–617 (2016).

    Article  CAS  PubMed  Google Scholar 

  103. Guedes, L. B., Tosoian, J. J., Hicks, J., Ross, A. E. & Lotan, T. L. PTEN loss in Gleason score 3 + 4 = 7 prostate biopsies is associated with nonorgan confined disease at radical prostatectomy. J. Urol. 197, 1054–1059 (2017).

    Article  PubMed  Google Scholar 

  104. Lokman, U., Erickson, A. M., Vasarainen, H., Rannikko, A. S. & Mirtti, T. PTEN loss but not ERG expression in diagnostic biopsies is associated with increased risk of progression and adverse surgical findings in men with prostate cancer on active surveillance. Eur. Urol. Focus https://doi.org/10.1016/j.euf.2017.03.004 (2017).

    Article  PubMed  Google Scholar 

  105. Mithal, P. et al. PTEN loss in biopsy tissue predicts poor clinical outcomes in prostate cancer. Int. J. Urol. 21, 1209–1214 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Shah, R. B., Bentley, J., Jeffery, Z. & DeMarzo, A. M. Heterogeneity of PTEN and ERG expression in prostate cancer on core needle biopsies: implications for cancer risk stratification and biomarker sampling. Hum. Pathol. 46, 698–706 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. Wobker, S. E. & Epstein, J. I. Differential diagnosis of intraductal lesions of the prostate. Am. J. Surg. Pathol. 40, e67–e82 (2016).

    Article  PubMed  Google Scholar 

  108. Epstein, J. I. & Herawi, M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J. Urol. 175, 820–834 (2006).

    Article  PubMed  Google Scholar 

  109. Tosoian, J. J., Alam, R., Ball, M. W., Carter, H. B. & Epstein, J. I. Managing high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical glands on prostate biopsy. Nat. Rev. Urol. 15, 55–66 (2018).

    Article  PubMed  Google Scholar 

  110. 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  PubMed  Google Scholar 

  111. Robinson, B. D. & Epstein, J. I. Intraductal carcinoma of the prostate without invasive carcinoma on needle biopsy: emphasis on radical prostatectomy findings. J. Urol. 184, 1328–1333 (2010).

    Article  PubMed  Google Scholar 

  112. Hickman, R. A. et al. Atypical intraductal cribriform proliferations of the prostate exhibit similar molecular and clinicopathologic characteristics as intraductal carcinoma of the prostate. Am. J. Surg. Pathol. 41, 550–556 (2017).

    Article  PubMed  Google Scholar 

  113. De Marzo, A. M., Haffner, M. C., Lotan, T. L., Yegnasubramanian, S. & Nelson, W. G. Premalignancy in prostate cancer: rethinking what we know. Cancer Prev. Res. 9, 648–656 (2016).

    Article  CAS  Google Scholar 

  114. Pettersson, A. et al. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol. Biomarkers Prev. 21, 1497–1509 EPI-12-0042 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Leinonen, K. A. et al. Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer. Cancer Epidemiol. Biomarkers Prev. 22, 2333–2344 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Fontugne, J. et al. Recurrent prostate cancer genomic alterations predict response to brachytherapy treatment. Cancer Epidemiol. Biomarkers Prev. 23, 594–600 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lahdensuo, K. et al. Loss of PTEN expression in ERG-negative prostate cancer predicts secondary therapies and leads to shorter disease-specific survival time after radical prostatectomy. Mod. Pathol. 29, 1565–1574 (2016).

    Article  CAS  PubMed  Google Scholar 

  118. Yoshimoto, M. et al. PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications. Genes Chromosomes Cancer 51, 149–160 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Yoshimoto, M. et al. Incorporation of flanking probes reduces truncation losses for fluorescence in situ hybridization analysis of recurrent genomic deletions in tumor sections [abstract]. Cancer Res. 73, 63 (2014).

    Google Scholar 

  120. Sangale, Z. et al. A robust immunohistochemical assay for detecting PTEN expression in human tumors. Appl. Immunohistochem. Mol. Morphol. 19, 173–183 (2011).

    CAS  Google Scholar 

  121. Chaux, A. et al. Loss of PTEN expression is associated with increased risk of recurrence after prostatectomy for clinically localized prostate cancer. Mod. Pathol. 25, 1543–1549 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Punnoose, E. A. et al. PTEN loss in circulating tumour cells correlates with PTEN loss in fresh tumour tissue from castration-resistant prostate cancer patients. Br. J. Cancer 113, 1225–1233 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wyatt, A. W. et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2, 1598–1606 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Xia, Y. et al. Copy number variations in urine cell free DNA as biomarkers in advanced prostate cancer. Oncotarget 7, 35818–35831 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Wyatt, A. W. et al. Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer. J. Natl Cancer Inst. 110, 78–86 (2017).

    Google Scholar 

  126. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03236688 (2017).

  127. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02438007 (2017).

  128. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03050866 (2017).

  129. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02853097 (2017).

  130. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02269982 (2018).

  131. Ferraldeschi, R. et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur. Urol. 67, 795–802 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Edlind, M. P. & Hsieh, A. C. PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. Asian J. Androl. 16, 378–386 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Dillon, L. M. & Miller, T. W. Therapeutic targeting of cancers with loss of PTEN function. Curr. Drug Targets 15, 65–79 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Thomas, C. et al. Synergistic targeting of PI3K/AKT pathway and androgen receptor axis significantly delays castration-resistant prostate cancer progression in vivo. Mol. Cancer Ther. 12, 2342–2355 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Marques, R. B. et al. High efficacy of combination therapy using PI3K/AKT inhibitors with androgen deprivation in prostate cancer preclinical models. Eur. Urol. 67, 1177–1185 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Schwartz, S. et al. Feedback suppression of PI3Kalpha signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kbeta. Cancer Cell 27, 109–122 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Armstrong, A. J. et al. Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer. Eur. J. Cancer 81, 228–236 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wei, X. X. et al. A phase I study of abiraterone acetate combined with BEZ235, a dual PI3K/mTOR inhibitor, in metastatic castration resistant prostate cancer. Oncol. 22, e503–e543 (2017).

    Article  CAS  Google Scholar 

  139. Massard, C. et al. Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer. Eur. J. Cancer 76, 36–44 (2017).

    Article  CAS  PubMed  Google Scholar 

  140. Chow, H. et al. A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer. Cancer 122, 1897–1904 (2016).

    Article  CAS  PubMed  Google Scholar 

  141. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02106507 (2017).

  142. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02125084 (2017).

  143. Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02833883 (2017).

  145. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01485861 (2018).

  146. de Bono, J. S. et al. PTEN loss as a predictive biomarker for the Akt inhibitor ipatasertib combined with abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC). Ann. Oncol. 27, 718O (2016).

    Google Scholar 

  147. Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Jia, S. et al. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454, 776–779 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01884285 (2018).

  150. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02215096 (2018).

  151. Mateo, J. et al. DNA repair in prostate cancer: biology and clinical implications. Eur. Urol. 71, 417–425 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Gonzalez-Billalabeitia, E. et al. Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov. 4, 896–904 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. van de Ven, A. L. et al. Nanoformulation of olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation. Mol. Cancer Ther. 16, 1279–1289 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Hopkins, B. D. et al. A secreted PTEN phosphatase that enters cells to alter signaling and survival. Science 341, 399–402 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wang, H. et al. Relevance and therapeutic possibility of PTEN-long in renal cell carcinoma. PLOS One 10, e114250 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Drake, C. G. Immunotherapy for prostate cancer: an emerging treatment modality. Urol. Clin. North Am. 37, 121–129 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Strasner, A. & Karin, M. Immune infiltration and prostate cancer. Front. Oncol. 5, 128 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Gannon, P. O. et al. Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients. J. Immunol. Methods 348, 9–17 (2009).

    Article  CAS  PubMed  Google Scholar 

  161. Si, T. G., Wang, J. P. & Guo, Z. Analysis of circulating regulatory T cells (CD4+CD25+CD127-) after cryosurgery in prostate cancer. Asian J. Androl. 15, 461–465 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Peng, W. et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).

    Article  CAS  PubMed  Google Scholar 

  163. Moussavi, M. et al. Oncolysis of prostate cancers induced by vesicular stomatitis virus in PTEN knockout mice. Cancer Res. 70, 1367–1376 (2010).

    Article  CAS  PubMed  Google Scholar 

  164. Champion, B. R., Fisher, K. & Seymour, L. A. PTENtial cause for the selectivity of oncolytic viruses? Nat. Immunol. 17, 225–226 (2016).

    Article  CAS  PubMed  Google Scholar 

  165. Pencik, J. et al. STAT3 regulated ARF expression suppresses prostate cancer metastasis. Nat. Commun. 6, 7736 (2015).

    Article  CAS  PubMed  Google Scholar 

  166. Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Toso, A. et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9, 75–89 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Cuzick, J. et al. Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer. Br. J. Cancer 108, 2582–2589 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Lotan, T. L. et al. PTEN loss detection in prostate cancer: comparison of PTEN immunohistochemistry and PTEN FISH in a large retrospective prostatectomy cohort. Oncotarget 8, 65566–65576 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Funding for this research was provided in part by a Transformative Impact Award from the Congressionally Directed Medical Research Program–Prostate Cancer Research Program (CDMRP-PCRP) (W81XWH-13-2-0070, H.I.S. and T.L.L.). T.L.L. was additionally supported by the NIH and National Cancer Institute (NCI) P30 Cancer Center Support Grant CA006973 and the Patrick Walsh Prostate Cancer Research Fund. H.I.S. was additionally supported by NIH and NCI Prostate SPORE Grant P50-CA92629, NIH and NCI P30 Cancer Center Support Grant CA008748, and the Prostate Cancer Foundation. T.J. and D.M.B. were funded by Prostate Cancer Canada and the Movember Foundation (Grant #T2014-01-PRONTO). T.J. was supported by a Transformative Pathology Fellowship funded by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario.

Author information

Authors and Affiliations

  1. Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada

    Tamara Jamaspishvili & David M. Berman

  2. Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada

    Tamara Jamaspishvili & David M. Berman

  3. Department of Urology, Johns Hopkins University, Baltimore, MD, USA

    Ashley E. Ross

  4. Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA

    Howard I. Scher

  5. Department of Pathology, Johns Hopkins University, Baltimore, MD, USA

    Angelo M. De Marzo & Tamara L. Lotan

  6. Department of Oncology, Johns Hopkins University, Baltimore, MD, USA

    Angelo M. De Marzo & Tamara L. Lotan

  7. Department of Pathology and Legal Medicine, University of Sao Paulo, Campus Universitario Monte Alegre, Ribeirão Preto, Brazil

    Jeremy A. Squire

Authors
  1. Tamara Jamaspishvili
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David M. Berman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashley E. Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Howard I. Scher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angelo M. De Marzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeremy A. Squire
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tamara L. Lotan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article, took part in discussions of the content, and wrote the manuscript. T.J., D.M.B., H.I.S., A.M.D.M., J.A.S., and T.L.L. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Tamara L. Lotan.

Ethics declarations

Competing interests

T.L.L. has received research support from Ventana Medical Systems. D.M.B. has received financial support from Myriad Genetics and Metamark Genetics.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jamaspishvili, T., Berman, D., Ross, A. et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol 15, 222–234 (2018). https://doi.org/10.1038/nrurol.2018.9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2018.9

This article is cited by

Search

Advanced 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