African-specific molecular taxonomy of prostate cancer

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a signifcant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1 . The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3 . Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Signifcant African-ancestry-specifc fndings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer diferentiated by ancestry and defned as global mutational subtypes (GMS). By further including Chinese Asian data, we confrm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specifc to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African–European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical beneft of including individuals of African ancestry, our GMS subtypes reveal diferent evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene–environment interaction—defned here as a diferent efect of an environmental surrounding in people with diferent ancestries or vice versa—we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies

African inclusion in prostate cancer genomic studies provides the first glimpses into addressing health disparities through tailored clinical care

No abstract available.Funding for genomic support provided by the National Health and Medical Research Council (NHMRC) of Australia.http://wileyonlinelibrary.com/journal/ctm2am2024School of Health Systems and Public Health (SHSPH)SDG-03:Good heatlh and well-bein

ANO7 African-ancestral genomic diversity and advanced prostate cancer

DATA AVAILABILITY : The data used in this study will be made available on request.BACKGROUND : Prostate cancer (PCa) is a significant health burden for African men, with mortality rates more than double global averages. The prostate specific Anoctamin 7 (ANO7) gene linked with poor patient outcomes has recently been identified as the target for an African-specific protein-truncating PCa-risk allele. METHODS : Here we determined the role of ANO7 in a study of 889 men from southern Africa, leveraging exomic genotyping array PCa case-control data (n = 780, 17 ANO7 alleles) and deep sequenced whole genome data for germline and tumour ANO7 interrogation (n = 109), while providing clinicopathologically matched European-derived sequence data comparative analyses (n = 57). Associated predicted deleterious variants (PDVs) were further assessed for impact using computational protein structure analysis. RESULTS : Notably rare in European patients, we found the common African PDV p.Ile740Leu (rs74804606) to be associated with PCa risk in our case-control analysis (Wilcoxon rank-sum test, false discovery rate/FDR = 0.03), while sequencing revealed co-occurrence with the recently reported African-specific deleterious risk variant p.Ser914* (rs60985508). Additional findings included a novel protein-truncating African-specific frameshift variant p.Asp789Leu, African-relevant PDVs associated with altered protein structure at Ca2+ binding sites, early-onset PCa associated with PDVs and germline structural variants in Africans (Linear regression models, −6.42 years, 95% CI = −10.68 to −2.16, P-value = 0.003) and ANO7 as an inter-chromosomal PCa-related gene fusion partner in African derived tumours. CONCLUSIONS : Here we provide not only validation for ANO7 as an African-relevant protein-altering PCa-risk locus, but additional evidence for a role of inherited and acquired ANO7 variance in the observed phenotypic heterogeneity and African-ancestral health disparity.The National Health and Medical Research Council (NHMRC) of Australia; Ideas Grant; USA Congressionally Directed Medical Research Programs (CDMRP) Prostate Cancer Research Program (PCRP) Idea Development Award; HEROIC Consortium Award and the Petre Foundation via the University of Sydney Foundation, Australia. Open Access funding enabled and organized by CAUL and its Member Institutions.http://www.nature.com/pcan/hj2024School of Health Systems and Public Health (SHSPH)SDG-03:Good heatlh and well-bein

Next generation mapping reveals novel large genomic rearrangements in prostate cancer

Complex genomic rearrangements are common molecular events driving prostate carcinogenesis. Clinical significance, however, has yet to be fully elucidated. Detecting the full range and subtypes of large structural variants (SVs), greater than one kilobase in length, is challenging using clinically feasible next generation sequencing (NGS) technologies. Next generation mapping (NGM) is a new technology that allows for the interrogation of megabase length DNA molecules outside the detection range of single-base resolution NGS. In this study, we sought to determine the feasibility of using the Irys (Bionano Genomics Inc.) nanochannel NGM technology to generate whole genome maps of a primary prostate tumor and matched blood from a Gleason score 7 (4 + 3), ETS-fusion negative prostate cancer patient. With an effective mapped coverage of 35X and sequence coverage of 60X, and an estimated 43% tumor purity, we identified 85 large somatic structural rearrangements and 6,172 smaller somatic variants, respectively. The vast majority of the large SVs (89%), of which 73% are insertions, were not detectable ab initio using high-coverage short-read NGS. However, guided manual inspection of single NGS reads and de novo assembled scaffolds of NGM-derived candidate regions allowed for confirmation of 94% of these large SVs, with over a third impacting genes with oncogenic potential. From this single-patient study, the first cancer study to integrate NGS and NGM data, we hypothesise that there exists a novel spectrum of large genomic rearrangements in prostate cancer, that these large genomic rearrangements are likely early events in tumorigenesis, and they have potential to enhance taxonomy.This work was supported by Movember Australia and the Prostate Cancer Foundation Australia (PCFA) as part of the Movember Revolutionary Team Award (MRTA) to the Garvan Institute of Medical Research program on prostate cancer bone metastasis (ProMis to P.I.C. and V.M.H.) dedicated to establishing NGM for clinically relevant prostate cancer, and the Australian Prostate Cancer Research Centre NSW (APCRC-NSW). Participant recruitment and sampling was supported by the Cancer Association of South Africa (CANSA to M.S.R.B and V.M.H.). W.J. is supported by APCRC-NSW, E.K.F.C. and D.C.P. are partly supported by ProMis, P.I.C. is supported by Mrs Janice Gibson and the Ernest Heine Family Foundation, Australia, and V.M.H. is supported by the University of Sydney Foundation and Petre Foundation, Australia.www.impactjournals.com/oncotargetam2018School of Health Systems and Public Health (SHSPH

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

Metagenomic analysis reveals a rich bacterial content in high‐risk prostate tumors from African men

BACKGROUND : Inflammation is a hallmark of prostate cancer (PCa), yet no pathogenic agent has been identified. Men from Africa are at increased risk for both aggressive prostate disease and infection. We hypothesize that pathogenic microbes may be contributing, at least in part, to high‐risk PCa presentation within Africa and in turn the observed ethnic disparity. METHODS : Here we reveal through metagenomic analysis of host‐derived wholegenome sequencing data, the microbial content within prostate tumor tissue from 22 men. What is unique about this study is that patients were separated by ethnicity, African vs European, and environments, Africa vs Australia. RESULTS : We identified 23 common bacterial genera between the African, Australian, and Chinese prostate tumor samples, while nonbacterial microbes were notably absent. While the most abundant genera across all samples included: Escherichia, Propionibacterium, and Pseudomonas, the core prostate tumor microbiota was enriched for Proteobacteria. We observed a significant increase in the richness of the bacterial communities within the African vs Australian samples (t = 4.6‐5.5; P = .0004‐.001), largely driven by eight predominant genera. Considering core human gut microbiota, African prostate tissue samples appear enriched for Escherichia and Acidovorax, with an abundance of Eubacterium associated with host tumor hypermutation. CONCLUSIONS : Our study provides suggestive evidence for the presence of a core, bacteria‐rich, prostate microbiome. While unable to exclude for fecal contamination, the observed increased bacterial content and richness within the African vs non‐ African samples, together with elevated tumor mutational burden, suggests the possibility that bacterially‐driven oncogenic transformation within the prostate microenvironment may be contributing to aggressive disease presentation in Africa.The Cancer Association of South Africa (CANSA) and National Research Foundation (NRF) of South Africa, as well as the Australian Prostate Cancer Research Center NSW (APCRC‐NSW) and St Vincent’s Prostate Cancer Center. VMH is supported by the University of Sydney Foundation and Petre Foundation, Australia and YF by the China Scholarship Council (#CSC201606325044)http://wileyonlinelibrary.com/journal/prosam2020School of Health Systems and Public Health (SHSPH

Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers

ADDITIONAL FILE 1: FIGURE S1. Concordant SV call generation from Manta and GRIDSS. FIGURE S2. Summary of SVs in each type, compared to other studies. FIGURE S3. CIRCOS plot of hyper-SV mutated tumours. FIGURE S4. The spread of SV breakpoints and samples in each 1 Mbp genomic bin. FIGURE S5. TMPRSS2-ERG fusion with interstitial region retention. TABLE S1. Clinical and pathological characteristics of 180 prostate cancer patients included in this study. TABLE S2. Biallelic assessment of CDK12 in hyper-duplicated samples. TABLE S3. Biallelic assessment of BRCA2 in hyper-deleted samples.ADDITIONAL FILE 2: TABLE S4. Summary of gene fusions identified from SVs. ADDITIONAL FILE 3: TABLE S5. SV calls resulting in gene fusions.DATA AND MATERIALS AVAILABILITY : The datasets analysed in this study were obtained and accessible through Jaratlerdsiri et al [6], with sequence data deposited in the European GenomePhenome Archive (EGA; https://ega-archive.org) under overarching accession EGAS00001006425 and including the Southern African Prostate Cancer Study (SAPCS) Dataset (EGAD00001009067) and Garvan/St Vincent’s Prostate Cancer Database (EGAD00001009066). The computational code used to analyse SV subtypes, SV hotspots and gene fusions is available on GitHub [68].BACKGROUND : African ancestry is a significant risk factor for advanced prostate cancer (PCa). Mortality rates in sub- Saharan Africa are 2.5-fold greater than global averages. However, the region has largely been excluded from the benefits of whole genome interrogation studies. Additionally, while structural variation (SV) is highly prevalent, PCa genomic studies are still biased towards small variant interrogation. METHODS : Using whole genome sequencing and best practice workflows, we performed a comprehensive analysis of SVs for 180 (predominantly Gleason score ≥ 8) prostate tumours derived from 115 African, 61 European and four ancestrally admixed patients. We investigated the landscape and relationship of somatic SVs in driving ethnic disparity (African versus European), with a focus on African men from southern Africa. RESULTS : Duplication events showed the greatest ethnic disparity, with a 1.6- (relative frequency) to 2.5-fold (count) increase in African-derived tumours. Furthermore, we found duplication events to be associated with CDK12 inactivation and MYC copy number gain, and deletion events associated with SPOP mutation. Overall, African-derived tumours were 2-fold more likely to present with a hyper-SV subtype. In addition to hyper-duplication and deletion subtypes, we describe a new hyper-translocation subtype. While we confirm a lower TMPRSS2-ERG fusion-positive rate in tumours from African cases (10% versus 33%), novel African-specific PCa ETS family member and TMPRSS2 fusion partners were identified, including LINC01525, FBXO7, GTF3C2, NTNG1 and YPEL5. Notably, we found 74 somatic SV hotspots impacting 18 new candidate driver genes, with CADM2, LSAMP, PTPRD, PDE4D and PACRG having therapeutic implications for African patients. CONCLUSIONS : In this first African-inclusive SV study for high-risk PCa, we demonstrate the power of SV interrogation for the identification of novel subtypes, oncogenic drivers and therapeutic targets. Identifying a novel spectrum of SVs in tumours derived from African patients provides a mechanism that may contribute, at least in part, to the observed ethnic disparity in advanced PCa presentation in men of African ancestry.The Medical Health and Medical Research Council (NHMRC) of Australia, University of Sydney Bridging Grant, the USA. Department of Defense (DoD) Prostate Cancer Research Program (PCRP) Idea Development.https://genomemedicine.biomedcentral.comam2023School of Health Systems and Public Health (SHSPH

African-specific molecular taxonomy of prostate cancer

Data availability DNA-sequencing data have been deposited at the European Genome- Phenome Archive (EGA) under overarching accession EGAS00001006425 and including the Southern African Prostate Cancer Study (SAPCS) Dataset (EGAD00001009067 and Garvan/St Vincent’s Prostate Cancer Database EGAD00001009066). Academic researchers meeting the data-access policy criteria may apply for data access through the respective data access committees. CPGEA data are available through http://www.cpgea.com. PCAWG data are available at ICGC Data Portal (https://dcc.icgc.org/releases/PCAWG).Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African–European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene–environment interaction—defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa—we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.The National Health and Medical Research Council (NHMRC) of Australia, NHMRC Ideas Grants, University of Sydney Bridging Grant, the US Department of Defense (DoD) Prostate Cancer Research Program (PCRP) Idea Development Award TARGET Africa.http://www.nature.com/natuream2023School of Health Systems and Public Health (SHSPH

Characterisation, diversity and evolution of the saltwater crocodile MHC

Abstract The saltwater crocodile (Crocodylus porosus) forms the basis of a crocodile farming industry for the international skin trade in Australia. For this industry, mortalities from stress and disease are common due to a compromise of the adaptive immunity. Currently the genetic understanding of the immune response is poor, which in turn impedes an understanding of genes, and hence genetic markers, affecting disease susceptibility. As a key component of adaptive immunity is the Major Histocompatibility Complex (MHC), this thesis characterises the MHC genes with an emphasis on the saltwater crocodile and assesses genetic diversity, evolutionary mechanisms that are influencing diversity and their roles in adaptive immunity. The genetic diversity among saltwater crocodiles showed the number of MHC variants within an individual ranging from one to seven, indicating that there are at least four gene loci in this species. An association between a certain MHC variant and Lymphoid proliferation/ Vasculitis/ Encephalitis in saltwater crocodiles was identified (P = 0.00007), suggesting genetic susceptibility to the disease. Phylogenetic analyses showed that MHC variants from 20 species of Crocodylia clustered at the genus or family level rather than in species-specific groups, indicating orthologous relationships. Selection detection analyses showed that balancing selection influenced some classes of MHC in Crocodylia. In addition, construction of Bacterial Artificial Chromosome scaffolds in the saltwater crocodile showed MHC class I genes located along with antigen processing genes and a framework gene. This would support structural variation of the saltwater crocodile MHC that differs from that expected in tetrapod ancestors. This project offers a better understanding of immunogenetics and immunogenomics in Crocodylia and presents recommendations for future research, where these findings could serve as a foundation in order to achieve a complete picture of MHC in Crocodylia

Data from: MHC class II diversity of koala (Phascolarctos cinereus) populations across their range

Major histocompatibility complex class II (MHCII) genes code for proteins that bind and present antigenic peptides and trigger the adaptive immune response. We present a broad geographical study of MHCII DA β1 (DAB) and DB β1 (DBB) variants of the koala (Phascolarctos cinereus; n=191) from 12 populations across eastern Australia, with a total of 13 DAB and 7 DBB variants found. We identified greater MHCII variation and, possibly, additional gene copies in koala populations in the north (Queensland and New South Wales) relative to the south (Victoria), confirmed by STRUCTURE analyses and genetic differentiation using analysis of molecular variance. The higher MHCII diversity in the north relative to south could potentially be attributed to (i) significant founder effect in Victorian populations linked to historical translocation of bottlenecked koala populations and (ii) increased pathogen-driven balancing selection and/or local genetic drift in the north. Low MHCII genetic diversity in koalas from the south could reduce their potential response to disease, although the three DAB variants found in the south had substantial sequence divergence between variants. This study assessing MHCII diversity in the koala with historical translocations in some populations contributes to understanding the effects of population translocations on functional genetic diversity