Prostate Cancer Genome Research Articles

Identification of BBC3 as a novel indicator for predicting prostate cancer development and olaparib resistance

Prostate cancer (PCa) is a commonly occurring malignancy in elderly men. Olaparib, a poly ADP-ribose polymerase inhibitor, is utilized in PCa treatment. However, patients often develop resistance to olaparib after a period of treatment. Genetic alterations may play a significant role in this resistance, but the specific genes involved remain unclear. This study collected RNA-sequence data from the Gene Expression Omnibus database on both olaparib-sensitive and -resistant PCa cells to identify genes crucial for resistance. Subsequently, the enriched pathways of these genes were analyzed, and a protein–protein interaction (PPI) network was constructed to identify hub genes. The effect of these hub genes on PCa occurrence, progression, and prognosis was assessed using data from The Cancer Genome Atlas and Chinese Prostate Cancer Genome and Epigenome Atlas databases. Finally, this study validated our findings in clinical PCa samples and cells. From the GSE189186 dataset, 50 upregulated genes and 2 downregulated genes were identified in olaparib-resistant C4-2B and LNCaP cells. Utilizing the PPI network, eight upregulated genes (BBC3, TP53I3, FDXR, DDB2, CDKN1A, GADD45A, ZMAT3, and SESN1) were identified as hub genes for olaparib-resistant PCa cells. Furthermore, some of these genes were central to PCa occurrence, with BBC3 also influencing progression and prognosis. Importantly, BBC3 expression was upregulated in clinical PCa samples and affected PCa cells sensitive to olaparib, suggesting its potential as a predictive marker for PCa development and olaparib resistance.

Exploration of the influence of GOLGA8B on prostate cancer progression and the resistance of castration-resistant prostate cancer to cabazitaxel

Castration-resistant prostate cancer (CRPC) represents the final stage of prostate cancer (PCa). Cabazitaxel, a taxane chemotherapy drug, is used in treating CRPC. However, patients with CRPC eventually develop resistance to cabazitaxel, and the underlying mechanism remains unclear. Here, we aimed to investigate potential genetic alterations that may play a role in CRPC resistance to cabazitaxel. Using microarray data from the GSE158494 dataset, we identified ten critical genes (CXCL8, ITGB8, CLIP4, MAP1B, WIPI1, MMP13, CXCL1, C1S, GOLGA8B, and CXCL6) associated with CRPC cell resistance to cabazitaxel. The potential function of these key genes in PCa progression was analyzed using different databases, including Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA). Our findings revealed altered expression of these genes in the development of PCa. Furthermore, CXCL1 and GOLGA8B were found to influence the disease-free survival (DFS) status of patients with PCa, with GOLGA8B affecting the overall prognosis in patients with PCa. Additionally, GOLGA8B expression was associated with the infiltration of various immune cells in PCa, and it was upregulated in clinical PCa and CRPC samples. Through CCK-8 assays, we established that GOLGA8B could influence the sensitivity of CRPC cells to cabazitaxel and docetaxel. In conclusion, we identified GOLGA8B as a crucial gene that influences PCa progression and contributes to CRPC resistance to cabazitaxel.

Abstract 1627: Persistence and dynamics of mutation, selection, and epistasis during the somatic evolution of low-risk, high-risk, and metastatic prostate cancer

Abstract Driver genes and mutations responsible for prostate cancer tumorigenesis have been identified, but research has not previously quantified the effects of prostate cancer driver mutations, or how the magnitude of those effects vary with cancer stage and epistatic interactions among genes. Using 2699 prostate cancer tumor exomes, genomes, and panel sequences (1648 primary tumors and 1051 metastatic samples), we calculated the cancer effect size (CES)—the each mutation confers to lower-risk (Grade Group 1/2) and higher-risk (Grade Group 3/4/5) tumorigenesis and metastasis. The lower-risk, higher-risk, and metastatic tumors exhibited similar neutral rates at which mutations were introduced into DNA, with these underlying gene mutation rates generally increasing from lower-risk to higher risk to metastatic tumors. However, lower risk, higher risk, and metastatic tumors noticeably differed in the genes and specific somatic variants that were most highly selected for within each group. Therefore, to assess whether differences in natural selection that we observed among low-risk, high-risk, and metastatic tumor types were at least partly due to epistatic interactions, we applied a model of pairwise epistasis that quantified the effect of the presence or absence of a mutation in one gene on the selection for mutations in another gene. We found significant evidence of epistatic effects among driver genes. Our results indicate a very early role for SPOP in the development of prostate cancer: strength of selection for SPOP mutations is tightly associated with the degree to which the mutation ablates contact with the BRD3, and these disruptive mutations in turn increase the selection for mutations in several other tumor suppressors and oncogenes such as RHOA. Previously identified gene-gene interactions such as that between SPOP and PIK3CA were supported by this analysis, and we also identified novel gene-gene interactions such as those between AR and MUC16 occurring during metastasis. In conclusion, we have demonstrated that rates of mutation and strengths of selection on these driver mutations vary dynamically along the trajectories to lower-risk, higher-risk, and metastatic prostate cancer, and that powerful selective epistasis among driver genes provides an explanation for these differences. Because precision therapeutic targeting of somatic variant genes is fundamentally targeting the selective benefit obtained from that variant at the time of treatment, understanding these changes in stage-specific and somatic genotype-specific selective strengths will enable better therapeutic targeting in translational and clinical science. Citation Format: Moein Rajaei, Alexander Yang, Christopher N. Cross, J Nick Fisk, Elizabeth B. Perry, Jeffrey D. Mandell, Stephen G. Gaffney, Takafumi N. Yamaguchi, Julie Livingstone, Vincent L. Cannataro, Peter Humphrey, Jose Costa, Paul C. Boutros, Jeffrey P. Townsend. Persistence and dynamics of mutation, selection, and epistasis during the somatic evolution of low-risk, high-risk, and metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1627.

Spatial architectures of somatic mutations in normal prostate, benign prostatic hyperplasia and coexisting prostate cancer

This study aimed to identify somatic mutations in nontumor cells (NSMs) in normal prostate and benign prostatic hyperplasia (BPH) and to determine their relatedness to prostate cancer (PCA). From 22 PCA patients, two prostates were sampled for 3-dimensional mapping (50 normal, 46 BPH and 1 PCA samples), and 20 prostates were trio-sampled (two normal or BPH samples and one PCA sample) and analyzed by whole-genome sequencing. Normal and BPH tissues harbored several driver NSMs and copy number alterations (CNAs), including in FOXA1, but the variations exhibited low incidence, rare recurrence, and rare overlap with PCAs. CNAs, structural variants, and mutation signatures were similar between normal and BPH samples, while BPHs harbored a higher mutation burden, shorter telomere length, larger clone size, and more private NSMs than normal prostates. We identified peripheral-zonal dominance and right-side asymmetry in NSMs, but the asymmetry was heterogeneous between samples. In one normal prostate, private oncogenic RAS-signaling NSMs were detected, suggesting convergence in clonal maintenance. Early embryonic mutations exhibited two distinct distributions, characterized as layered and mixed patterns. Our study identified that the BPH genome differed from the normal prostate genome but was still closer to the normal genome than to the PCA genome, suggesting that BPH might be more related to aging or environmental stress than to tumorigenic processes.

Dissecting transcription of the 8q24-MYC locus in prostate cancer recognizes the equilibration between androgen receptor direct and indirect dual-functions

BackgroundAndrogen receptor (AR) activation and repression dual-functionality only became known recently and still remains intriguing in prostate cancer (PCa). MYC is a prominent oncogene that functionally entangles with AR signaling in PCa. Further exploration of AR regulatory mechanisms on MYC gene transcription bears clinical and translation significance.MethodsBioinformatics analysis of PCa cell line and clinical RNA-Seq and ChIP-Seq (chromatin immunoprecipitation-sequencing) datasets to anchor interactions of AR and MYC transcriptional networks. ChIP-qPCR and 3C (chromosome conformation capture) analyses to probe MYC distal regulation by AR binding sites (ABSs). CRISPR/Cas9-mediated genome-editing to specify functions of ABS within the 8q24-MYC locus on androgen-mediated MYC transcription. Global FoxA1 and HoxB13 distribution profiling to advance AR transcriptional mechanisms.ResultsHere we recognize AR bi-directional transcription mechanisms by exploiting the prominent 8q24-MYC locus conferring androgen hyper-sensitivity. At ~ 25 Kb downstream of the MYC gene, we identified an undefined ABS, P10. By chromatin analyses, we validated androgen-dependent spatial interaction between P10 and MYC-Promoter (MYC-Pro) and temporal epigenetic repression of these MYC-proximal elements. We next designed a CRISPR/Cas9-mediated double genomic knock-out (KO) strategy to show that P10-KO slightly lessened androgen-elicited MYC transrepression in LNCaP-AR cells. In similar genomic editing assays, androgen-mediated MYC repression became slightly deepened upon KO of P11, an ABS in the PVT1 gene locus highly enriched in AR-binding motifs and peaks. We also investigated multiple ABSs in the established PCAT1 super-enhancer that distally interacts with MYC-Pro for transactivation, with each KO pool consistently shown to relieve androgen-elicited MYC repression. In the end, we systemically assessed androgen effects in the 8q24-MYC locus and along PCa genome to generalize H3K27ac and BRD4 re-distribution from pioneer factors (FoxA1 and HoxB13) to AR sites.ConclusionTogether, we reconciled these observations by unifying AR dual-functions that are mechanistically coupled to and equilibrated by co-factor redistribution.Graphical

Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer.

The discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co-factor competition and redistribution. Indeed, AR dual functions are exemplified by locus-wide regulation of the oncogenic 8q24-MYC region. RT-qPCR assay and public RNA-profiling datasets were used to assess MYC transcription in androgen-sensitive cell lines. Public ChIP-seq and RNA-Seq datasets were computed to evaluate AR-MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross-talks. Bio-informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen-elicited distal regulation. Finally, co-factor re-distribution were globally tracked between AR and MYC binding sites. In this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen-mediated versus MYC-mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen-repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR-binding site and MYC-binding site. Together, our findings stratified AR-MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.

Combining next-generation hormonal therapy with PARP inhibition in metastatic castration-resistant prostate cancer

In a paradigm of precision oncology, elegant preclinical work showed that inhibition of poly(ADP-ribose) polymerase (PARP) proteins can exploit a deficiency of cancer cells to repair DNA double-strand breaks through homologous recombination repair (HRR), 1 Lord CJ Ashworth A PARP inhibitors: synthetic lethality in the clinic. Science. 2017; 355: 1152-1158 Crossref PubMed Scopus (1411) Google Scholar and the resulting synthetic lethality was first shown to be clinically effective in ovarian cancer carrying a germline deleterious mutation in BRCA1 or BRCA2, key HRR genes. 2 Banerjee S Moore KN Colombo N et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021; 22: 1721-1731 Summary Full Text Full Text PDF PubMed Scopus (92) Google Scholar For prostate cancer, the discovery of alterations in BRCA2 and other HRR-related genes in up to 20% of advanced disease 3 Robinson D Van Allen EM Wu YM et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161: 1215-1228 Summary Full Text Full Text PDF PubMed Scopus (2077) Google Scholar led to the development of several biomarker-driven trials of PARP inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) 4 Abida W Patnaik A Campbell D et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020; 38: 3763-3772 Crossref PubMed Scopus (309) Google Scholar , 5 de Bono JS Mehra N Scagliotti GV et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021; 22: 1250-1264 Summary Full Text Full Text PDF PubMed Scopus (79) Google Scholar , 6 Hussain M Mateo J Fizazi K et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020; 383: 2345-2357 Crossref PubMed Scopus (289) Google Scholar , 7 Smith MR Scher HI Sandhu S et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2022; 23: 362-373 Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar and to the regulatory approval of rucaparib and olaparib as monotherapy for the treatment of mCRPC harbouring mutations in BRCA2 and other HRR genes. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trialTalazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations. Full-Text PDF

Metastasis-Directed Therapy for Oligometastatic Castration-Sensitive Prostate Cancer: An Alternative to ADT?

The standard treatment of patients with metastatic prostate cancer is systemic treatment with androgen-deprivation therapy (ADT). The spectrum-based model of metastatic disease includes the presence of an oligometastatic state, an intermediary between localized and widespread metastatic disease, in which radical local treatment might improve systemic control. Our purpose is to review the literature on metastasis-directed therapy in the treatment of oligometastatic prostate cancer. Several prospective clinical trials have reported improvements in ADT-free survival and progression-free survival with metastasis-directed therapy of oligometastatic prostate cancer. Retrospective studies have found improvements in oncologic outcomes for patients with oligometastatic prostate cancer undergoing metastasis-directed therapy, and several recent prospective clinical trials have confirmed these results. Advancements in imaging as well as an understanding of the genomics of oligometastatic prostate cancer may allow for better patient selection for metastasis-directed therapy and the potential for cure in selected patients.

Long non-coding RNA ENST00000503625 is a potential prognostic biomarker and metastasis suppressor gene in prostate cancer.

Dysregulation of Long Non-coding RNAs (lncRNAs) emerges to be a hallmark of cancers. Metastatic prostate cancer and localized disease that recurs after treatment are clinical challenges, it remains unclear how lncRNA plays a role in those processes. From previous RNA-Seq data on 65 prostate cancer and adjacent normal tissues. We identified a novel lncRNA ENST00000503625 down-regulated in prostate cancer and correlated with tumor progression characteristics. Public datasets were examined for associations between ENST00000503625 expression and clinical parameters and prognoses. Subsequently, we constructed and externally validated a nomogram for predicting biochemical recurrence (BCR). Finally, in vitro experiments were carried out to determine how ENST00000503625 functions biologically in prostate cancer. Low ENST00000503625 in tumor was associated with poor clinical features and prognoses. TCGA pan-cancer analysis found that ENST00000503625 was deregulated in a variety of tumors and correlated with overall survival, disease-specific survival, and progression-free survival. The nomogram for predicting BCR was constructed using TCGA data, which exhibited excellent accuracy in external validation with Chinese Prostate Cancer Genome and Epigenome Atlas data. Gene Ontology and KEGG pathway analysis found that genes related to ENST00000503625 were enriched in multiple tumor progression related pathways. When ENST00000503625 was knocked down in vitro, the epithelial-mesenchymal transition was induced, by which cancer cells migrated and invaded more readily. Our data suggested that ENST00000503625 may serve as a potential prognostic marker or a therapeutic target for prostate cancer metastases.

Effect of Selenium and Lycopene on Radiation Sensitivity in Prostate Cancer Patients Relative to Controls.

Almost half of prostate cancer (PC) patients receive radiation therapy as primary curative treatment. In spite of advances in our understanding of both nutrition and the genomics of prostate cancer, studies on the effects of nutrients on the radiation sensitivity of PC patients are lacking. We tested the hypothesis that low plasma levels of selenium and lycopene have detrimental effects on ionising radiation-induced DNA damage in prostate cancer patients relative to healthy individuals. The present study was performed in 106 PC patients and 132 age-matched controls. We found that the radiation-induced micronucleus (MN) and nuclear buds (NBuds) frequencies were significantly higher in PC patients with low selenium (p = 0.008 and p = 0.0006 respectively) or low lycopene (p = 0.007 and p = 0.0006 respectively) levels compared to the controls. The frequency of NBuds was significantly higher (p < 0.0001) in PC patients who had low levels of both selenium and lycopene compared to (i) controls with low levels of both selenium and lycopene and (ii) PC patients with high levels of both selenium and lycopene (p = 0.0001). Our results support the hypothesis that low selenium and lycopene levels increase the sensitivity to radiation-induced DNA damage and suggest that nutrition-based treatment strategies are important to minimise the DNA-damaging effects in PC patients receiving radiotherapy.

CCNB1 and AURKA are critical genes for prostate cancer progression and castration-resistant prostate cancer resistant to vinblastine.

Prostate cancer (PCa) is a common malignancy occurring in men. As both an endocrine and gonadal organ, prostate is closely correlated with androgen. So, androgen deprivation therapy (ADT) is effective for treating PCa. However, patients will develop castration-resistant prostate cancer (CRPC) stage after ADT. Many other treatments for CRPC exist, including chemotherapy. Vinblastine, a chemotherapeutic drug, is used to treat CRPC. However, patients will develop resistance to vinblastine. Genetic alterations have been speculated to play a critical role in CRPC resistance to vinblastine; however, its mechanism remains unclear. Various databases, such as Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA), were used to collect the RNA-sequence data of PCa and CRPC patients and vinblastine-resistant PCa cells. Using online tools, Metascape and TIMER, the pathways and immune infiltration associated with vinblastine resistance-related genes in PCa were analyzed. The function of these genes was verified in clinical samples and CRPC cells. Using GSE81277 dataset, we collected the RNA-sequence data of vinblastine sensitive and resistant LNCaP cells and found nine genes (CDC20, LRRFIP1, CCNB1, GPSM2, AURKA, EBLN2, CCDC150, CENPA and TROAP) that correlated with vinblastine resistance. Furthermore, CCNB1, GPSM2 and AURKA were differently expressed between normal prostate and PCa tissues, even influencing PCa progression. The GSE35988 dataset revealed that CCNB1 and AURKA were upregulated in PCa and CRPC samples. Various genes were also found to affect the survival status of PCa patients based on TCGA. These genes were also related to immune cell infiltration. Finally, we verified the function of CCNB1 and AURKA and observed that they were upregulated in PCa and CRPC clinical samples and increased the sensitivity of CRPC cells to vinblastine. CCNB1 and AURKA are central to CRPC resistance to vinblastine and affect PCa progression.

Review of prostate cancer genomic studies in Africa.

Prostate cancer (PCa) is the second most commonly diagnosed in men worldwide and one of the most frequent cancers in men in Africa. The heterogeneity of this cancer fosters the need to identify potential genetic risk factors/biomarkers. Omics variations may significantly contribute to early diagnosis and personalized treatment. However, there are few genomic studies of this disease in African populations. This review sheds light on the status of genomics research on PCa in Africa and outlines the common variants identified thus far. The allele frequencies of the most significant SNPs in Afro-native, Afro-descendants, and European populations were compared. We advocate how these few but promising data will aid in understanding, better diagnosing, and precisely treating this cancer and the need for further collaborative research on the genomics of PCa in the African continent.

Implicancias clínicas de la biología molecular del cáncer de próstata: Artículo de revisión

To understand the term genomic heterogeneity in prostate cancer, we must understand the clonal genomic evolution of cancer, as well as knowing that it is a dynamic and evolutionary phenomenon. Knowing the genome of prostate cancer not only allows us to have a vision over time of the genomic alterations that occur during its different stages, but also to learn about the mechanisms of metastasis. In addition, knowing the hereditary component of prostate cancer allows the evaluation of patients and to be able to identify if we are dealing with a family at risk.

Genetics and genomics of prostate cancer and therapeutic implications

Genetics and genomics of prostate cancer and therapeutic implications

Comparative genomics of primary prostate cancer and paired metastases: insights from 12 molecular case studies.

Primary prostate cancer (PCa) can show marked molecular heterogeneity. However, systematic analyses comparing primary PCa and matched metastases in individual patients are lacking. We aimed to address the molecular aspects of metastatic progression while accounting for the heterogeneity of primary PCa. In this pilot study, we collected 12 radical prostatectomy (RP) specimens from men who subsequently developed metastatic castration‐resistant prostate cancer (mCRPC). We used histomorphology (Gleason grade, focus size, stage) and immunohistochemistry (IHC) (ERG and p53) to identify independent tumors and/or distinct subclones of primary PCa. We then compared molecular profiles of these primary PCa areas to matched metastatic samples using whole‐exome sequencing (WES) and amplicon‐based DNA and RNA sequencing. Based on combined pathology and molecular analysis, seven (58%) RP specimens harbored monoclonal and topographically continuous disease, albeit with some degree of intratumor heterogeneity; four (33%) specimens showed true multifocal disease; and one displayed monoclonal disease with discontinuous topography. Early (truncal) events in primary PCa included SPOP p.F133V (one patient), BRAF p.K601E (one patient), and TMPRSS2:ETS rearrangements (eight patients). Activating AR alterations were seen in nine (75%) mCRPC patients, but not in matched primary PCa. Hotspot TP53 mutations, found in metastases from three patients, were readily present in matched primary disease. Alterations in genes encoding epigenetic modifiers were observed in several patients (either shared between primary foci and metastases or in metastatic samples only). WES‐based phylogenetic reconstruction and/or clonality scores were consistent with the index focus designated by pathology review in six out of nine (67%) cases. The three instances of discordance pertained to monoclonal, topographically continuous tumors, which would have been considered as unique disease in routine practice. Overall, our results emphasize pathologic and molecular heterogeneity of primary PCa, and suggest that comprehensive IHC‐assisted pathology review and genomic analysis are highly concordant in nominating the ‘index’ primary PCa area. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

GENOMICS OF PROSTATE CANCER: CLINICAL UTILITY AND CHALLENGES.

The studying of prostate cancer genomics is important for understanding prostate cancer biology, it can provide clinically relevant stratification into subtypes, the development of new prognostic and predictive markers in the context of precision medicine, and the development of new targeted therapies. Recent studies have provided detailed insight into genomics, epigenomics and proteomics of prostate cancer, both primary and metastatic castration-resistant (mCRPC). Many mutations have been discovered, both those that occur early in the carcinogenesis and progression as well as those responsible for the resistance to therapy occurring later under the influence of treatment. A large number of characteristic mutated signaling pathways has been identified, e.g. the mutations in DNA repair pathway were found in 23% of mCRPC, which suggests potential response to PARP inhibitors. Multifocality and intralesional genomic heterogeneity of prostate cancer make the clinical application of genomics complicated. Although a great progress was made in understanding prostate cancer genomic, and clinical studies related to its routine application are ongoing, prostate cancer genomics still needs to find its standard wide routine application in patients with prostate cancer.

Prostate Cancer Genomics Research Disparities in Africa: Advancing Knowledge in Resource Constrained Settings.

Prostate cancer disproportionately affects men of African descent and it is estimated that Africa will bear the highest disease burden in the next decade. Underlying genomic factors may contribute to prostate cancer disparities; however, it is unclear whether Africa has prioritised genomics research toward addressing these disparities. A Pubmed review was performed of publications spanning a 15-year period, with specific focus on prostate cancer genomics research that included samples from Africa and investigators in Africa. Data are presented on research publications from Africa relative to similar publications from different geographical regions, and more specifically, the extent of disparities and the contributions to prostate cancer knowledge as a result of genomics research that included African samples and African institutions. Limited publication output may reflect the infrastructure and funding challenges in Africa. Widespread cooperation should be fostered by sharing capacity and leveraging existing expertise to address the growing cancer burden facing the continent.

Differences in Prostate Cancer Genomes by Self-reported Race: Contributions of Genetic Ancestry, Modifiable Cancer Risk Factors, and Clinical Factors.

Black men die from prostate cancer twice as often as White men, a disparity likely due to inherited genetics, modifiable cancer risk factors, and healthcare access. It is incompletely understood how and why tumor genomes differ by self-reported race and genetic ancestry. Among 2,069 men with prostate cancer (1,841 self-reported White, 63 Asian, 165 Black) with access to clinical-grade sequencing at the same cancer center, prevalence of tumor and germline alterations was assessed in cancer driver genes reported to have different alteration prevalence by race. Clinical characteristics such as prostate-specific antigen and age at diagnosis as well as cancer stage at sample procurement differed by self-reported race. However, most genomic differences persisted when adjusting for clinical characteristics. Tumors from Black men harbored fewer PTEN mutations and more AR alterations than those from White men. Tumors from Asian men had more FOXA1 mutations and more ZFHX3 alterations than White men. Despite fewer TP53 mutations, tumors from Black men had more aneuploidy, particularly chromosome arm 8q gains, an adverse prognostic factor. Genetic ancestry was associated with similar tumor alterations as self-reported race, but also with modifiable cancer risk factors. Community-level average income was associated with chr8q gains after adjusting for race and ancestry. Tumor genomics differed by race even after accounting for clinical characteristics. Equalizing access to care may not fully eliminate such differences. Therapies for alterations more common in racial minorities are needed. Tumor genomic differences should not be assumed to be entirely due to germline genetics.

The Interplay Between Prostate Cancer Genomics, Metabolism, and the Epigenome: Perspectives and Future Prospects.

Prostate cancer is a high-incidence cancer, often detected late in life. The prostate gland is an accessory gland that secretes citrate; an impaired citrate secretion reflects imbalances in the activity of enzymes in the TCA Cycle in mitochondria. Profiling studies on prostate tumours have identified significant metabolite, proteomic, and transcriptional modulations with an increased mitochondrial metabolic activity associated with localised prostate cancer. Here, we focus on the androgen receptor, c-Myc, phosphatase and tensin Homolog deleted on chromosome 10 (PTEN), and p53 as amongst the best-characterised genomic drivers of prostate cancer implicated in metabolic dysregulation and prostate cancer progression. We outline their impact on metabolic function before discussing how this may affect metabolite pools and in turn chromatin structure and the epigenome. We reflect on some recent literature indicating that mitochondrial mutations and OGlcNAcylation may also contribute to this crosstalk. Finally, we discuss the technological challenges of assessing crosstalk given the significant differences in the spatial sensitivity and throughput of genomic and metabolomic profiling approaches.

Androgen Receptor Signaling in Prostate Cancer Genomic Subtypes.

Simple SummaryApproximately 1 in 8 men will be diagnosed with prostate cancer (PCa) at some point in their lifetime. Five-year survival rate for patients with local or regionally spread disease is near 100%, but this drops to 30% when the cancer has spread to distant sites. Androgen receptor (AR) signaling plays a pivotal role in normal prostate development and PCa cell survival. Therapies targeting the AR pathway are mainline treatments, but resistance is a major clinical problem. From the literature and our own meta-analysis of PCa databases, we aimed to review the connections between PCa genetic alterations and the AR signaling axis at the primary stage. Assessing how combinations of PCa genetic drivers that arise in patients affect AR signaling will aid in stratifying patients who will likely respond to AR-directed therapies, and those who will require other therapeutic agents upfront in order to prevent disease progression.While many prostate cancer (PCa) cases remain indolent and treatable, others are aggressive and progress to the metastatic stage where there are limited curative therapies. Androgen receptor (AR) signaling remains an important pathway for proliferative and survival programs in PCa, making disruption of AR signaling a viable therapy option. However, most patients develop resistance to AR-targeted therapies or inherently never respond. The field has turned to PCa genomics to aid in stratifying high risk patients, and to better understand the mechanisms driving aggressive PCa and therapy resistance. While alterations to the AR gene itself occur at later stages, genomic changes at the primary stage can affect the AR axis and impact response to AR-directed therapies. Here, we review common genomic alterations in primary PCa and their influence on AR function and activity. Through a meta-analysis of multiple independent primary PCa databases, we also identified subtypes of significantly co-occurring alterations and examined their combinatorial effects on the AR axis. Further, we discussed the subsequent implications for response to AR-targeted therapies and other treatments. We identified multiple primary PCa genomic subtypes, and given their differing effects on AR activity, patient tumor genetics may be an important stratifying factor for AR therapy resistance.