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Advances in Prognostic Methylation Biomarkers for Prostate Cancer

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Advances in Prognostic Methylation Biomarkers for Prostate Cancer cancers Review Advances in Prognostic Methylation Biomarkers for Prostate Cancer 1 1,2 1,2, 1,2, , Dilys Lam , Susan Clark , Clare Stirzaker y and Ruth Pidsley * y 1 Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia; [email protected] (D.L.); [email protected] (S.C.); [email protected] (C.S.) 2 St. Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales 2010, Australia * Correspondence: [email protected]; Tel.: +61-2-92958315 These authors have contributed equally. y Received: 22 September 2020; Accepted: 13 October 2020; Published: 15 October 2020 Simple Summary: Prostate cancer is a major cause of cancer-related death in men worldwide. There is an urgent clinical need for improved prognostic biomarkers to better predict the likely outcome and course of the disease and thus inform the clinical management of these patients. Currently, clinically recognised prognostic markers lack sensitivity and specificity in distinguishing aggressive from indolent disease, particularly in patients with localised, intermediate grade prostate cancer. Thus, there is major interest in identifying new molecular biomarkers to complement existing standard clinicopathological markers. DNA methylation is a frequent alteration in the cancer genome and offers potential as a reliable and robust biomarker. In this review, we provide a comprehensive overview of the current state of DNA methylation biomarker studies in prostate cancer prognosis. We highlight advances in this field that have enabled the discovery of novel prognostic genes and discuss the potential of methylation biomarkers for noninvasive liquid-biopsy testing. Abstract: There is a major clinical need for accurate biomarkers for prostate cancer prognosis, to better inform treatment strategies and disease monitoring. Current clinically recognised prognostic factors, including prostate-specific antigen (PSA) levels, lack sensitivity and specificity in distinguishing aggressive from indolent disease, particularly in patients with localised intermediate grade prostate cancer. There has therefore been a major focus on identifying molecular biomarkers that can add prognostic value to existing markers, including investigation of DNA methylation, which has a known role in tumorigenesis. In this review, we will provide a comprehensive overview of the current state of DNA methylation biomarker studies in prostate cancer prognosis, and highlight the advances that have been made in this field. We cover the numerous studies into well-established candidate genes, and explore the technological transition that has enabled hypothesis-free genome-wide studies and the subsequent discovery of novel prognostic genes. Keywords: DNA methylation; epigenetics; biomarkers; circulating DNA; cfDNA; prostate cancer; early detection; prognosis 1. Introduction Prostate cancer (PCa) is the most commonly diagnosed noncutaneous cancer in men and one of the leading causes of cancer death in males. Globally, 1,276,106 new cases were diagnosed in 2018 alone [1,2], and this number is projected to rise by approximately 80%, to more than two million new cases a year, by 2040 [3–5]. Currently, PCa diagnosis is achieved through assessment of blood prostate-specific antigen (PSA) levels, digital rectal examination (clinical T-stage) and histological examination of needle Cancers 2020, 12, 2993; doi:10.3390/cancers12102993 www.mdpi.com/journal/cancers Cancers 2020, 12, x 2 of 39 Cancers 2020, 12, 2993 2 of 38 prostate-specific antigen (PSA) levels, digital rectal examination (clinical T-stage) and histological examination of needle biopsies (Gleason Score (GS)/ISUP Grade) [6]. PSA-based screening was biopsiesintroduced (Gleason in the Scorelate 198 (GS)0s, /andISUP has Grade) significantly [6]. PSA-based increased screening the earlywas detection introduced of localized in the disease late 1980s, and[7–9 has]. Diagnosis significantly at this increased early organ the-confined early detection stage of of disease localized is crucial disease as [it7 –is9 ].pot Diagnosisentially curable at this by early organ-confinedradical prostatectomy stage of(RP disease), a procedure is crucial to surgically as it is potentially remove the curable whole byprostate radical gland. prostatectomy While this is (RP), acurative procedure for tomost surgically prostate remove cancers, the wholeapproximately prostate 30% gland. of Whilepatients this treated is curative by RP for mostexperience prostate cancers,biochemical approximately recurrence 30%(BCR of) [ patients10], and treated17–22% byof RPthese experience relapsed biochemicalpatients progress recurrence to metastatic (BCR) [-10], andlethal 17–22% PCa [11 of–13 these]. There relapsed is therefore patients a need progress to identify to metastatic-lethal the men at high PCa risk [of11 metastatic–13]. There progression, is therefore a needso that to additional identify the interventions men at high can risk be of offered metastatic earlier progression, (e.g., adjuvant so that therapies additional such interventionsas chemotherapy can be oandffered radiotherapy earlier (e.g.,) [14 adjuvant]. therapies such as chemotherapy and radiotherapy) [14]. OnOn thethe otherother hand, many men men diagnosed diagnosed with with PCa PCa have have an an indolent indolent form form of ofthe the disease, disease, which which isischaracterised characterised by slow progression progression with with no no eventual eventual clinical clinical manifestation manifestation [15 [,1516,].16 For]. For these these men men,, RPRP representsrepresents anan overtreatmentovertreatment givengiven the risk of unnecessary side effects effects and and compromised compromised quality quality of lifeof life [17 ,[1817].,18 Thus,]. Thus strategies, strategies such such as as ‘watchful ‘watchful waiting’ waiting’ and and ‘active ‘active surveillance’ surveillance’ have have emerged emerged for for men diagnosedmen diagnosed with lowwith grade low disease,grade disease, in which in regularwhich monitoringregular monitoring is used tois detectused to tumour detect progression, tumour withprogression, the aim ofwith delaying the aim RPof delaying until it is RP clinically until it is necessary clinically [necessary19]. However, [19]. However, 13–45% of 13 low-risk–45% of low men- on activerisk men surveillance on active exhibit surveillance a PSA exhibit rise and a progressPSA rise to and surgery progress or other to surgery treatments or other [20– 22treatments], indicating [20– that 22], indicating that they may have been inappropriately assigned to monitoring, and should have they may have been inappropriately assigned to monitoring, and should have been treated earlier. been treated earlier. PCa has a heterogeneous clinical course which makes it challenging to decide the most appropriate PCa has a heterogeneous clinical course which makes it challenging to decide the most treatment or monitoring strategy for individual patients [23]. There is a major unmet clinical need for appropriate treatment or monitoring strategy for individual patients [23]. There is a major unmet specific prognostic biomarkers that can accurately differentiate indolent from aggressive tumours that clinical need for specific prognostic biomarkers that can accurately differentiate indolent from are likely to metastasise and lead to lethal disease [24]. The ability to identify the risk of progression at aggressive tumours that are likely to metastasise and lead to lethal disease [24]. The ability to identify initialthe risk diagnosis of progressio wouldn informat initial decisions diagnosis about would personalized inform decisions treatment about and personalized/or monitoring treatment strategies, asand/or well asmonitoring the use of adjuvantstrategies, therapy, as well for as improved the use clinicalof adjuvant management therapy, and for enhanced improved outcomes clinical for PCamanagement patients (Figureand enhanced1). outcomes for PCa patients (Figure 1). FigureFigure 1.1. Schematic showing showing the the pathway pathway for for the the application application of ofbiomarkers biomarkers for for improved improved prognostic prognostic stratificationstratification in prostate cancer cancer patients. patients. Prostate Prostate cancer cancer is isa aheterogeneous heterogeneous disease disease and and identifying identifying thosethose patients at at diagnosis diagnosis that that have have aggressive aggressive vs indolent vs. indolent disease diseaseis critical is in critical informing in informingthe clinical the clinicalmanagement management of these ofpatients. these patients.Biological sampling Biological includes sampling tissue includes biopsies, tissue and biopsies, blood and and urine blood andsamples. urine These samples. are Theseassayed are using assayed molecular using molecularbiomarkers, biomarkers, including includingDNA mutations, DNA mutations, DNA DNAmethylation methylation and transcription, and transcription, and clinicopa and clinicopathologicalthological markers, markers,such as GS/ISUP such as grade GS/ISUP and tumour grade and staging. The ultimate goal is to improve the prognostic stratification of patients to inform the optimal tumour staging. The ultimate goal is to improve the prognostic stratification of patients to inform treatment strategies for prostate cancer patients. TNM: tumour/nodes/metastasis staging; PSA: the optimal treatment strategies for prostate cancer patients. TNM: tumour/nodes/metastasis
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