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

Effectiveness of hospital-wide methicillin-resistant Staphylococcus aureus (MRSA) infection control policies differs by ward specialty.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of preventable nosocomial infections and is endemic in hospitals worldwide. The effectiveness of infection control policies varies significantly across hospital settings. The impact of the hospital context towards the rate of nosocomial MRSA infections and the success of infection control is understudied. We conducted a modelling study to evaluate several infection control policies in surgical, intensive care, and medical ward specialties, each with distinct ward conditions and policies, of a tertiary public hospital in Sydney, Australia. We reconfirm hand hygiene as the most successful policy and find it to be necessary for the success of other policies. Active screening for MRSA, patient isolation in single-bed rooms, and additional staffing were found to be less effective. Across these ward specialties, MRSA transmission risk varied by 13% and reductions in the prevalence and nosocomial incidence rate of MRSA due to infection control policies varied by up to 45%. Different levels of infection control were required to reduce and control nosocomial MRSA infections for each ward specialty. Infection control policies and policy targets should be specific for the ward and context of the hospital. The model we developed is generic and can be calibrated to represent different ward settings and pathogens transmitted between patients indirectly through health care workers. This can aid the timely and cost effective design of synergistic and context specific infection control policies

A multilevel systems approach for effective public health actions

The complex and multilevel nature of health has made it challenging to evaluate public health actions. Performing comparative analyses in different contexts is particularly challenging. Health care associated infections are a public health threat in need of more effective hospital infection control. They are associated with significant morbidity and mortality worldwide and place a large burden on health care resources. Hospital infection control has had mixed success, with many aspects of context playing a large role. As such, systems approaches are called for that improve the capability to capture multilevel determinants, context and complex and causal interrelationships (such as feedback and nonlinearity) that may change over time.In this thesis a novel ‘multilevel systems approach’ is proposed that appears capable of complex, multilevel and causal analysis. The approach draws together qualitative and quantitative concepts and methods from four multilevel systems theories and methodologies: the Realist approach, Systems Thinking, Health System Frameworks and System Modelling and Simulation. The power and feasibility of the approach to analyse and evaluate complex public health actions in different contexts is examined by its specific application to hospital infection control. In particular, to the control of Methicillin-resistant Staphylococcus aureus (MRSA), a health care associated multidrug-resistant infection.In doing so, the context-specific (and nonlinear) effects of competing hospital infection control policies on changing trends in the incidence rate and prevalence of MRSA were measured and compared. The capability to evaluate multiple infection control policies implemented in different and interacting ward settings simultaneously, had not previously been demonstrated. This subsequently provided valuable insights. Given the contribution and generalisability of the multilevel systems approach, its application toward a range of public health actions is recommended

The daily prevalence of MRSA in surgical wards (blue), intensive care wards (red), short-stay medical wards (green), and long-stay medical wards (black) of one hospital, from April 2008 to December 2009, averaged over 1000 simulations.

<p>The daily prevalence of MRSA in surgical wards (blue), intensive care wards (red), short-stay medical wards (green), and long-stay medical wards (black) of one hospital, from April 2008 to December 2009, averaged over 1000 simulations.</p

The incidence rate of MRSA per 10,000 overnight bed days (OBD), averaged over 1000 simulations, in response to changes in both staff hand hygiene (HH) compliance and hand hygiene efficacy in (A) surgical, (B) intensive care, (C) short-stay medical, and (D) long-stay medical wards.

<p>The colours indicate the MRSA incidence rate per 10,000 OBD. The dark blue area represents the combination of hand hygiene compliance and efficacy ranges that achieved incidence rates of less than 10 cases per 10,000 OBD.</p

The effect of active surveillance (A and F), ward staffing levels or health care worker (HCW) to patient ratios (B and G), staff contact cohorting (C and H), patient isolation (D and I), and staff hand hygiene compliance (E and J) on the average daily prevalence and incidence rate per 10,000 overnight bed days (OBD) of MRSA, in surgical (blue), intensive care (red), short-stay medical (green), and long-stay medical (black) wards, in 2008 and 2009, averaged over 1000 simulations.

<p>The effect of active surveillance (A and F), ward staffing levels or health care worker (HCW) to patient ratios (B and G), staff contact cohorting (C and H), patient isolation (D and I), and staff hand hygiene compliance (E and J) on the average daily prevalence and incidence rate per 10,000 overnight bed days (OBD) of MRSA, in surgical (blue), intensive care (red), short-stay medical (green), and long-stay medical (black) wards, in 2008 and 2009, averaged over 1000 simulations.</p

A model of health care worker (HCW) and patient flow dynamics through hospital ward specialties and rooms.

<p>Solid arrows represent HCW and patient movement into, out of, and between ward specialties and rooms, and between MRSA susceptible and colonised states. Dashed arrows represent MRSA transmission occurring upon contact between HCWs and patients. When beds in single-bed rooms (SBR) or multiple-bed rooms (MBR) are not available, hospital patient admissions may be delayed and inpatients that are being moved from a ward or room remain in their current bed until the requested beds are made available.</p