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The Genetic Complexity of Prostate Cancer

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The Genetic Complexity of Prostate Cancer G C A T T A C G G C A T genes Review The Genetic Complexity of Prostate Cancer Eva Compérat 1,2,3,*, Gabriel Wasinger 3 , André Oszwald 3 , Renate Kain 3 , Geraldine Cancel-Tassin 1 and Olivier Cussenot 1,4 1 CeRePP/GRC5 Predictive Onco-Urology, Sorbonne University, 75020 Paris, France; [email protected] (G.C.-T.); [email protected] (O.C.) 2 Department of Pathology, Hôpital Tenon, Sorbonne University, 75020 Paris, France 3 Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; [email protected] (G.W.); [email protected] (A.O.); [email protected] (R.K.) 4 Department of Urology, Hôpital Tenon, Sorbonne University, 75020 Paris, France * Correspondence: [email protected]; Tel.: +33-658246024 Received: 28 September 2020; Accepted: 23 November 2020; Published: 25 November 2020 Abstract: Prostate cancer (PCa) is a major concern in public health, with many genetically distinct subsets. Genomic alterations in PCa are extraordinarily complex, and both germline and somatic mutations are of great importance in the development of this tumor. The aim of this review is to provide an overview of genetic changes that can occur in the development of PCa and their role in potential therapeutic approaches. Various pathways and mechanisms proposed to play major roles in PCa are described in detail to provide an overview of current knowledge. Keywords: prostate cancer; germline mutations; somatic mutations; PTEN; TMPRSS2; ERG; androgen receptors 1. Introduction Prostate cancer (PCa) is a major concern in public health, with more than 1.1 million cases worldwide detected every year [1]. Several risk factors for developing PCa are known, e.g., older age, family history and African ethnicity. Despite the refinement of existing treatments and emergence of new management strategies, such as active surveillance and focal therapy, metastatic disease is frequent and mortality is still relatively high, with 26,730 estimated deaths in 2017 [2]. Based on the severity of disease at diagnosis according to differentiation, extension and stage, PCa may be treated in different ways; of particular importance is its initial hormone dependency which allows specific treatments, especially during early-stage disease [1]. Further differences exist between primary, metastatic (mPCa) and castration resistant PCa (CRPCa). Therefore, it is important to know the most important actors, especially the important role of genetics in this hormone-sensitive cancer. Several studies showed many different genetically distinct subsets of PCa. Various drivers are known, such as androgen-related fusions of ETS-related gene (ERG) and ETS family members, speckle-type pox virus and zinc finger protein (SPOP) mutations, DNA hypermethylation, PIK3/RAS/RAF pathway alterations and DNA damage repair (DDR) pathways. For better understanding, it is necessary to mention genetic screening, which was explored in the early 2000s and abandoned in 2012 after it was demonstrated that many of the detected PCa were clinically insignificant and did not affect patient life expectancy [3]. In recent years, powerful genetic tests were developed that provide polygenic risk scores for individual patients [4,5]. However, a remaining challenge is the recrudescence of clinically relevant PCa, which may also benefit from personalized approaches for risk assessment or therapy. Genes 2020, 11, 1396; doi:10.3390/genes11121396 www.mdpi.com/journal/genes Genes 2020, 11, 1396 2 of 12 Genes 2020, 11, x FOR PEER REVIEW 2 of 12 Despite recent advances, standard pathology remains a fundamental tool in managing PCa. The GleasonDespite score recent (GS), advances, reflecting standard tumor pathology differentiation, remains a fundamental is a staple of tool clinical in managing decision-making, PCa. The andGleason recent meetings score (GS) could, reflecting refine tumor the consensus differentiation, and diminish is a staple interobserver of clinical decision variability-making [6]., Nevertheless,and recent GS alonemeetings will could not give refine all the necessaryconsensus information;and diminish molecular interobserver profiling variability of PCa [6] could. Nevertheless, provide furtherGS information.alone will Fornot give instance, all the a necessary study by information Haffner et al.; molecular [7] showed profiling that metastasisof PCa could was provide not strictly further and mayinformation. result from For a tumor instance, region a study with by lower Haffner grade, et al alongside. [7] showed observing that metasta PTENsis loss. was Cliniciansnot strictly needand to be increasinglymay result from aware a tumor that althoughregion with classical lower grade, histopathology alongside observing is a firmly PTEN established loss. Clinicians basis forneed clinical to decisions,be increasingly it is not theaware single that determinantalthough classical of PCa histopathology behavior. is a firmly established basis for clinical decisions,In recent it studies is not the taking single a determinant scrutinous approach of PCa behavior to Gleason. grading of PCa, pathologists showed that cribriformIn recent and studies intraductal taking a PCa,scrutinous which approach should to be Gleason considered grading Gleason of PCa, grade pathologists 4, were show probablyed morethat aggressive cribriform than and theintraductal classical PCa, Gleason which grade should 4 pattern.be considere Moreover,d Gleason several grade studies 4, were underlined probably a more aggressive than the classical Gleason grade 4 pattern. Moreover, several studies underlined a more aggressive behavior of cribriform PCa, partly explained by the underlying molecular aberrations more aggressive behavior of cribriform PCa, partly explained by the underlying molecular in these tumor patterns. A recent study tested genomic instability by determining the portion of aberrations in these tumor patterns. A recent study tested genomic instability by determining the the genome altered and somatic copy number alterations (CNA). Patients with cribriform and/or portion of the genome altered and somatic copy number alterations (CNA). Patients with cribriform intraductal PCa and GS 7 had significantly higher percentages of the genome altered than men and/or intraductal ≥PCa and ≥ GS 7 had significantly higher percentages of the genome altered than withoutmen thiswithout pattern this inpattern both cohortsin both cohorts of The Cancerof The Cancer Genome Genome Atlas (TCGA)Atlas (TCGA (2.2 fold;) (2.2p fold;= 0.0003) p = 0.0003) and the Canadianand the Prostate Canadian Cancer Prostate Genome Cancer Network Genome (CPC-GENE) Network (CPC (1.7-GENE fold; p) =(1.70.004) fold; [ 8p]. = These 0.004) patterns [8]. These were associatedpatterns with were deletions associated of with different deletions chromosomes, of different suchchromosomes as 8p, 16q,, such 10q23, as 8p, 13q22, 16q, 17p1310q23, and13q22, 1q22, and17p13 amplification and 1q22 of, 8q24,and amplification which plays of a major8q24, rolewhich in PCaplays evolution a major role and in is specificallyPCa evolution addressed and is in thisspecifically review. CNAs addressed comprised in this a total review of 1299. CNAs gene comprised deletionsand a total 369 amplificationsof 1299 gene deletions in the TCGA and dataset.369 Severalamplifications of the affected in the genes TCGA were dataset. known Several to be of associated the affected with genes aggressive were known prostate to be cancer, associated such with as loss of PTEN,aggressive CDH1 prostate and BCAR1 cancer and, such gain as ofloss MYC. of PTEN, Point mutationsCDH1 and in BCAR TP53,1 SPOPand gain and FOXA1of MYC. were Point also associatedmutations with in theseTP53, PCaSPOP patterns and FOXA1 but occurredwere also lessassociated frequently with thanthese CNAs.PCa patterns This study but occurred clearly less shows thatfrequently cribriform than/intraductal CNAs. This patterns study areclearly associated shows that with cribriform/intraductal increased genomic pattern instability,s are clusteringassociated to with increased genomic instability, clustering to genetic regions involved in aggressive PCa. genetic regions involved in aggressive PCa. The very complex genomic situation of PCa can be broken down into two major aspects, which The very complex genomic situation of PCa can be broken down into two major aspects, which need need to be considered, namely, the germline genetic background and the somatic changes in PCa to be considered, namely, the germline genetic background and the somatic changes in PCa (Figure1). (Figure 1). FigureFigure 1. Common 1. Common genomic genomic alterations alterations in prostatein prostate cancer. cancer Germline. Germline mutations mutations are are highlighted highlighted in in blue, whileblue, typical while somatic typical somatic mutations mutations are highlighted are highlighted in orange. in orange. For abbreviations For abbreviations see fullsee full text. text. Genes 2020, 11, 1396 3 of 12 2. Germline Mutations Driving PCa Hereditary prostate cancer (HPC) is defined by strict clinical criteria and represents 5% of all newly diagnosed PCa [9]. Inherited predisposition to acquire PCa is genetically determined by the presence of a deleterious mutation of DNA repair genes also related to breast/ovarian cancers (i.e., BRCA1 and BRCA2, ATM, etc.) or PCa-specific risk genes (HOXB13 and 8q24 region) [10]. A recent study performed germline sequencing and analysis of DNA repair genes [11] in 5545 men of European ancestry, including 2775 nonaggressive
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