Differential genome-wide DNA methylation in prostate tumours from South African men

Background: DNA methylation is an epigenetic mechanism known to aid the progression of cancer, including prostate cancer. It is part of a cluster of molecular processes that initiate tumorigenesis and drive its early evolution by altering other molecular processes. While studies have looked at DNA methylation in prostate cancer, most have been limited by targeted gene analysis, with further bias towards non-African cohorts. Considering the enhanced coverage of more recent genome-wide arrays, such as the Illumina Infinium HumanMethylationEPIC BeadChip, which measures DNA methylation over more than 850,000 CpG sites genome-wide, many studies that have employed a more global approach to DNA methylation analysis are further limited by frequently utilising lower-coverage arrays. Due to the bias against African cohorts, African-relevant bioinformatic tools for the processing of African DNA methylation data, particularly generated by the EPIC array, are scarce. As a result, the genomic mechanisms that underlie African prostate cancer as well as the contribution of DNA methylation alterations to African prostate cancer are poorly understood. Results: Working with EPIC DNA methylation data, I present a novel established African-relevant genome-wide bioinformatic pipeline for the processing and normalisation of African tumour-derived genome-wide DNA methylation data. Pilot application of this pipeline on prostate tissue identified differentially methylated CpG dinucleotides that may contribute to aggressive prostate cancer in a small cohort of men of South African ancestry. Additionally, I identified top genes in South African prostate cancer that are significantly enriched for differentially methylated CpG sites. Finally, patient-matched genomic-epigenomic data integration revealed preliminary evidence for interplay between these two systems in African prostate cancer, although the identification of DNA methylation signatures would prove more insightful. Conclusions: Ultimately, this work highlights the marginalization of Africans in scientific research. As a preliminary solution to this underrepresentation, this dissertation provides a novel toolset to appropriately handle African DNA methylation data with the ultimate goal of generating a deeper understanding of the genomic mechanisms harboured within African prostate cancer, a field with limited knowledge. Potential improvements to this tool, complications encountered when interpreting epigenome-wide results as well as the near future of cancer genomics is discussed.Dissertation (MSc (Human Genetics))--University of Pretoria, 2021.Australian National Health and Medical Research CouncilGeneticsMSc (Human Genetics)Unrestricte

Alterations in the epigenetic machinery associated with prostate cancer health disparities

DATA AVAILABILITY STATEMENT : Data used in this study were published by Jaratlerdsiri et al., 2022, and made accessible via the European Genome-Phenome Archive (EGA; https://ega-archive.org, accessed on 1 June 2022) under study accession EGAS00001006425 and dataset accession EGAD00001009067 (Southern African Prostate Cancer Study, SAPCS) and EGAD00001009066 (Garvan/St. Vincent’s Prostate Cancer Study).SUPPLEMENTARY MATERIALS : FIGURE S1: Optimal cluster number identification; FIGURE S2: Consensus heatmap for variant data overlapping epigenetic machinery genes based on results from ten multi-omics integrative clustering algorithms with the assigned cluster numbers of (A) k = 3 and (B) k = 8; FIGURE S3: Silhouette plot quantifying Sample Similarity based on results from ten multi-omics integrative clustering algorithms with the assigned cluster numbers of (A) k = 3 and (B) k = 8; FIGURE S4: Mutational burden in African- and European-derived tumors; FIGURE S5: Damaging variant mutational burden in African- and European-derived tumors; TABLE S1: Patient Summary or African and European Study participants; TABLE S2: SuperPaths and their associated pathways included in this Study for their relationship to epigenetic processes; TABLE S3: List of genes assigned to Epigenetic Process Group 1 (chromatin organization and regulation); TABLE S4: List of genes assigned to Epigenetic Process Group 2 (histone modifications); TABLE S5: List of genes assigned to Epigenetic Process Group 3 (DNA methylation); TABLE S6: List of genes assigned to Epigenetic Process Group 4 (RNA regulation); TABLE S7: List of genes assigned to Epigenetic Process Group 5 (epigenetic regulation of gene expression); TABLE S8: MOVICS clustering results; TABLE S9: Statistical Summary for tumor mutational burden (per Mb) based on all coding variants in epigenetic machinery genes in African- and European-derived tumors; TABLE S10: Statistical Summary for tumor mutational burden (per Mb) based only on damaging variants (as per functional impact prediction) in epigenetic machinery genes in African- and European-derived tumors; TABLE S11: Independent test of epigenetic cancer Subtype (ECS) and Small Somatic mutation to compare mutation frequency; TABLE S12: Independent test of epigenetic cancer Subtype (ECS) and Structural variation to compare Structural variation frequency; TABLE S13: Clinical Summary based on hierarchical clustering results, with epigenetic cancer Subtype (ECS) as the grouping variable; TABLE S14: Top features, posterior probability, and rank order for joint analysis of Small Somatic mutation, Somatic Structural variant, and Somatic copy number alteration data identified by iClusterBayes; TABLE S15: Clinical Summary based on hierarchical clustering results for Somatic copy number alteration data only, with epigenetic copy number cancer Subtype (EcnCS) as the grouping variable.African ancestry is a significant risk factor for aggressive prostate cancer (PCa), with southern African ethnicity conferring a nearly 3-fold increased global risk for associated mortality. It is well understood that epigenetic alterations drive PCa initiation and progression, coupled with somatic alterations in genes encoding epigenetic enzymes. However, differences in the somatic alterations in these genes in African- versus European-derived prostate tumors and how they may contribute to PCa health disparities has yet to be investigated, which forms the objective of this study. With current PCa care almost exclusively based on and tailored for men of European ancestry, the identification of African-specific novel PCa epigenetic cancer drivers (n = 18), including therapeutic potential (6/18), offers clinical significance with the possibility of improving healthcare approaches and health outcomes for men of African ancestry.Prostate cancer is driven by acquired genetic alterations, including those impacting the epigenetic machinery. With African ancestry as a significant risk factor for aggressive disease, we hypothesize that dysregulation among the roughly 656 epigenetic genes may contribute to prostate cancer health disparities. Investigating prostate tumor genomic data from 109 men of southern African and 56 men of European Australian ancestry, we found that African-derived tumors present with a longer tail of epigenetic driver gene candidates (72 versus 10). Biased towards African-specific drivers (63 versus 9 shared), many are novel to prostate cancer (18/63), including several putative therapeutic targets (CHD7, DPF3, POLR1B, SETD1B, UBTF, and VPS72). Through clustering of all variant types and copy number alterations, we describe two epigenetic PCa taxonomies capable of differentiating patients by ancestry and predicted clinical outcomes. We identified the top genes in African- and European-derived tumors representing a multifunctional “generic machinery”, the alteration of which may be instrumental in epigenetic dysregulation and prostate tumorigenesis. In conclusion, numerous somatic alterations in the epigenetic machinery drive prostate carcinogenesis, but African-derived tumors appear to achieve this state with greater diversity among such alterations. The greater novelty observed in African-derived tumors illustrates the significant clinical benefit to be derived from a much needed African-tailored approach to prostate cancer healthcare aimed at reducing prostate cancer health disparities.The US Congressionally Directed Medical Research Programs (CDMRP) Prostate Cancer Research Program (PCRP) Idea Development Award, the Health Equity Research Outcomes Integrity Consortium (HEROIC) Award, the National Health and Medical Research Council (NHMRC) of Australia Project Grant and Ideas Grants, a Cancer Association of South Africa (CANSA) Development Gran, the National Research Foundation of South Africa andthe Petre Foundation, Australia.https://www.mdpi.com/journal/cancershj2023School of Health Systems and Public Health (SHSPH

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570