Genetics and genomics of prostate cancer and therapeutic implications - Antonarakis - 2022 - The Prostate - Wiley Online Library

Genetics and genomics of prostate cancer and therapeutic implications - Antonarakis - 2022 - The Prostate - Wiley Online Library

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Genetics and genomics of prostate cancer and therapeutic implications

Emmanuel S. Antonarakis MD

5-6 minutes

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First published: 03 June 2022

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Over the last 5 years, there has been an exponential increase in our understanding and characterization of the germline and somatic molecular landscapes of prostate cancer. This has led to a clearer appreciation of the genetic, genomic, transcriptomic, and (phospho)proteomic drivers of localized and advanced prostate cancers, as well as the evolutionary changes that occur at the molecular level as prostate cancer transitions from a hormone-sensitive disease to a castration-resistant disease. Some of these new insights have provided broad prognostic information to our patients with prostate cancer, while others have led to precision therapeutics whereby a particular drug or class of drugs shows enhanced efficacy against a specific mutation or genomic signature. Further, other molecular markers may serve to aid treatment selection, where a patient faces a dichotomous decision in his treatment journey.

In this Theme Issue of the journal, we will explore the clinical and treatment implications of prostate cancer genetics and genomics in eight segments. 

• The issue begins with a review of prostate cancer germline genetics, by Khan et al.,¹ who summarize the germline alteration landscape in patients with localized and advanced prostate cancer, review current consensus guidelines on germline testing, outline the prognostic and therapeutic implications, and highlight clinical trial opportunities for men who carry germline variants. 
• This is followed by an article by Cotter et al.² reviewing the somatic genomic landscape of advanced prostate cancer, pointing out some pitfalls and limitations when interpreting somatic mutation results, outlining some of the recent technological advances in next-generation sequencing assays, and concluding with some insights about SPOP mutations and their clinical implications. 
• The next article, by Kwan et al.,³ discusses genomic alterations in the AR pathway, the types and classes of molecular alterations affecting the AR gene, interrogation of AR genotype using liquid (circulating tumor DNA) biopsies, and the clinical correlates of different classes of AR alterations. 
• After that, Graham et al.⁴ review the importance of detecting mismatch repair deficiency or microsatellite instability in prostate cancer, discuss the clinical approval of pembrolizumab in this context, point out some important caveats when assessing for mismatch repair deficiency, and outline some mechanisms of immunotherapy sensitivity and resistance in this context. 
• Next, Cresta Morgado et al.⁵ review the clinical implications of homologous repair deficiency (particularly BRCA1/2 mutations and others), outline the role of poly (ADP-ribose) polymerase inhibitors in this setting, and discuss some of the pitfalls in defining homologous recombination deficiency in clinical practice. 
• The next article is by Choudhury,⁶ who discusses the prevalence and relevance of alterations in the PTEN–PI3K pathway in advanced prostate cancer, reviews some of the recent clinical agents targeting this pathway, outlines some of the challenges with developing drugs in this context, and discusses some combination strategies (and biomarker selection) for rational therapy development. 
• This is followed by a summary of genomic biomarkers that inform radiotherapeutic approaches, by Sutera et al.,⁷ who outline some of the most clinically useful DNA- and RNA-based prognostic markers of radiotherapy efficacy, while they also review the emerging field of sensitivity markers for PSMA-targeted radioligand therapies. 
• Finally, the issue comes to a close with an article by Mizuno et al.⁸ outlining some novel technologies for studying the epigenome, reviewing the various analytes from which molecular studies can be performed (tissue, circulating tumor DNA, circulating tumor cells, extracellular vesicles), and providing some future directions on where the field will be going moving forward.

All in all, this Theme Issue will update us about the state-of-the-science as it relates to molecular landscapes of prostate cancer, and will be of interest to a wide audience including basic scientists, genomics experts, technology developers, informaticians and computational biologists, genetic counselors, molecular pathologists, as well as clinicians (oncologists, urologists, and radiation oncologists) managing patients with localized and advanced prostate cancer. I hope that you enjoy reading the issue as much as I did, and that you find it educational and inspiring. And a hearty congratulations to all of the authors for putting together an outstanding issue!

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