Clinical implications of pten loss in prostate cancer

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

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support SIMILAR CONTENT BEING VIEWED BY OTHERS CLINICAL IMPLICATIONS OF GENOMIC ALTERATIONS IN METASTATIC PROSTATE CANCER Article 15 January 2021 DIFFERENTIAL IMPACT OF TUMOR SUPPRESSOR

GENE (_TP53, PTEN, RB1_) ALTERATIONS AND TREATMENT OUTCOMES IN METASTATIC, HORMONE-SENSITIVE PROSTATE CANCER Article Open access 22 July 2021 EARLY-ONSET METASTATIC AND CLINICALLY ADVANCED

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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 * Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada Tamara Jamaspishvili & David M. Berman * Department

of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada Tamara Jamaspishvili & David M. Berman * Department of Urology, Johns Hopkins University,

Baltimore, MD, USA Ashley E. Ross * Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA Howard

I. Scher * Department of Pathology, Johns Hopkins University, Baltimore, MD, USA Angelo M. De Marzo & Tamara L. Lotan * Department of Oncology, Johns Hopkins University, Baltimore, MD,

USA Angelo M. De Marzo & Tamara L. Lotan * Department of Pathology and Legal Medicine, University of Sao Paulo, Campus Universitario Monte Alegre, Ribeirão Preto, Brazil Jeremy A. Squire

Authors * Tamara Jamaspishvili View author publications You can also search for this author inPubMed Google Scholar * David M. Berman View author publications You can also search for this

author inPubMed Google Scholar * Ashley E. Ross View author publications You can also search for this author inPubMed Google Scholar * Howard I. Scher View author publications You can also

search for this author inPubMed Google Scholar * Angelo M. De Marzo View author publications You can also search for this author inPubMed Google Scholar * Jeremy A. Squire View author

publications You can also search for this author inPubMed Google Scholar * Tamara L. Lotan View author publications You can also search for this author inPubMed 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 POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG.

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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).

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