38 research outputs found
Metagenomic analysis reveals a rich bacterial content in highârisk 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 highârisk PCa presentation within Africa and in turn
the observed ethnic disparity.
METHODS : Here we reveal through metagenomic analysis of hostâderived 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 = 4.6â5.5; P = .0004â.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,
bacteriaârich, prostate microbiome. While unable to exclude for fecal contamination, the observed increased bacterial content and richness within the African vs nonâ
African samples, together with elevated tumor mutational burden, suggests the
possibility that bacteriallyâdriven 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 (APCRCâNSW) and St Vincentâs 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 Vincentâs 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 â„ 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 Vincentâs 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 AfricanâEuropean-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 geneâenvironment interactionâdefined here as a different effect of an environmental surrounding in people with different ancestries or vice versaâwe 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
Germline variation at 8q24 and prostate cancer risk in men of European ancestry
Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (pâ<â4.28âĂâ10â15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CIâ=â3.62â4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification
Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants
Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe
Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan
Abstract: The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes
Superior Biochemical Recurrence and Long-term Quality-of-life Outcomes Are Achievable with Robotic Radical Prostatectomy After a Long Learning Curve-Updated Analysis of a Prospective Single-surgeon Cohort of 2206 Consecutive Cases
Our earlier analysis suggested that robot-assisted radical prostatectomy (RARP) achieved superiority over open radical prostatectomy (ORP) in terms of positive surgical margin (PSM) rates and functional outcomes. With larger sample size and longer follow-up, the objective of this study update is to assess whether our previous findings are upheld and whether the improved PSM rates for RARP after an initial learning curve compared with ORP-as observed in our earlier analysis-ultimately resulted in improved biochemical control. Prospective observational study comparing two surgical techniques; 2271 consecutive men underwent RARP (1520) or ORP (751) at a single centre from 2006 to 2016. Demographic and clinicopathological data were prospectively collected. The EPIC-QOL questionnaire was administered at baseline and 1.5, 3, 6, 12, and 24 mo. Multivariate linear regression modelled the difference in quality of life (QOL) domains against case number; logistic and Cox regression modelled the differences in PSM and biochemical recurrence (BCR) hazard ratios (HR), respectively. A total of 2206 men were included in BCR/PSM analysis and 1045 consented for QOL analysis. Superior pT2 surgical margins, early and late sexual outcomes, and early urinary outcomes were upheld and became more robust (narrowing of 95% confidence intervals [CIs]). The risk of BCR was initially higher for RARP, improved after 191 RARPs, and was 35% lower (hazard ratio [HR] 0.65, 95% CI 0.47-0.90) at final RARP, plateauing after 226 RARPs. Improved late (12-24 mo) urinary bother scores (adjusted mean difference [AMD]=4.7, 95% CI 1.3-8.0) and irritative-obstructive scores (AMD=3.8, 95% CI 0.9-5.6) at final RARP were demonstrated. Limitations include observational single surgeon data, possible residual confounding, and short follow-up. The results from this updated analysis demonstrate that RARP can be beneficial for patients of high-volume surgeons, although more randomised studies and studies with survival outcomes are needed. Robot-assisted radical prostatectomy was able to improve functional and oncological outcomes in this single surgeon's learning curv
Extraprostatic extension (EPE) of prostatic carcinoma : is its proximity to the surgical margin or Gleason score important?
Objective: To examine the association between histopathological factors of extraprostatic prostate cancer and outcome. Patients and Methods: Patients with extraprostatic extension (EPE) without positive margins, seminal vesicle or lymph node involvement were analysed from a consecutive radical prostatectomy cohort of 1136 (2002â2006) for: (i) distance of EPE from the margin; (ii) Gleason score of the EPE; and (iii) extent of EPE. Log-rank, KaplanâMeier, and Cox regression analyses were performed. Results: The study included 194 pT3a, pN0, R0 patients with a median follow-up of 5.4 years, with 37 (19%) patients experiencing biochemical relapse (BCR). On univariable analysis, patients with a Gleason score of â„8 in the extraprostatic portion showed increased incidence of BCR compared with those with Gleason scores of â€7 (P = 0.03). The proximity of the EPE to the margin (0.01â7.5âmm) did not correlate with BCR. On multivariable analysis, the extent of EPE, the Gleason score of the dominant nodule or of the EPE portion did not correlate with BCR. Conclusion: Data from this study using current International Society of Urological Pathology Gleason scoring and EPE criteria indicate that close proximity of EPE to the margin is not associated with recurrence. Gleason score â„8 within EPE is associated with an increased BCR risk on univariable analysis, but larger studies are required to confirm whether extensive Gleason pattern 4 in an EPE indicates increased risk in an otherwise overall Gleason score 7 cancer.8 page(s
Prostate cancer in 432 men aged <50 years in the prostate-specific antigen era: a new outlook
Objective: To evaluate the clinical presentation and treatment outcomes of prostate cancer (PCa) in 432 consecutive patients aged < 50Â years in the prostate-specific antigen (PSA) era. Methods: Retrospective analysis was performed on all patients with PCa (14Â 570) from the years 1994 to 2017. A total of 432 consecutive patients aged < 50 years were identified. The patients were stratified by D'Amico risk groups, and their clinical presentation and treatment outcomes were analysed. The rates of biochemical recurrence after surgery were compared with the D'Amico prediction model as well as with older propensity-score-matched patients. The surgical pathology results in patients undergoing active surveillance (AS) were compared with those of low-risk patients who underwent immediate surgery. Results: A total of 44%, 42% and 13% of patients harboured low-risk, intermediate-risk and high-risk PCa, respectively. Their median age was 47Â years and a positive family history of PCa was reported in 39.1%. Clinical stage was T1 in 65.5% and T2 in 30.0% of patients, and 2.0% of patients had metastatic disease at presentation. Radical prostatectomy (RP) was performed in 78.4% of patients (n = 339) and the biochemical recurrence rates were 7.8% (low-risk), 15.3% (intermediate-risk) and 23.3% (high-risk) at 5Â years post-surgery. These rates were lower than expected according to the D'Amico prediction model or when compared with older matched patients. A total of 74 patients with low-risk PCa underwent AS and only 17.6% (n = 13) required radical treatment after a median follow-up of 46Â months. The surgical pathology results in patients undergoing ASdid not differ significantly from patients with low-risk PCa who underwent immediate surgery (positive surgical margins [P = 0.145], tumour volume [P = 0.257] or seminal vesicle involvement [P = 0.100]). Of the present cohort, only 0.4% died from PCa during a median follow-up of 65Â months. Conclusions: The clinical presentation and prognosis of young patients has changed dramatically during the PSA era. Patients nowadays present with lower-risk disease that can be treated adequately, with reassuring biochemical recurrence rates at 5Â years post-surgery. AS appears to be safe in patients with low-risk. PCa
Outcomes for active surveillance are similar for men with favourable risk ISUP-2 to those with ISUP-1 prostate cancer: A pair matched cohort study
Objective: To compare medium-term outcomes of active surveillance (AS) for men with favourable risk International Society for Urologic Pathology (ISUP)-2 prostate cancer (PCa) to a pair matched group of men with ISUP-1 PCa. Methods: This was a retrospective analysis of prospectively collected data from a single institution clinical outcomes registry, using propensity score matching. Men enrolled on AS with favourable risk ISUP-2 PCa with minimum 5-year follow-up were 1:2 propensity score matched to men with ISUP-1 disease. We assessed rates of progression to treatment, metastatic disease, adverse surgical pathology and overall survival. Results: Fifty-five ISUP-2 patients were matched to 105 ISUP-1 patients by propensity score. Median follow-up was 81 months (interquartile range (IQR), 61â109 months). Fifty-seven per cent in the ISUP-1 group progressed to treatment versus 58% in the ISUP-2 group (KM log rank p = 0.24). Estimated 1-, 2- and 5-year progression free survival rates were 93%, 60% and 33% for ISUP-1 patients and 94%, 63% and 16% for ISUP-2 patients, respectively. No patient from either group died of PCa. There was no statistical difference in rates of adverse pathology or metastatic disease between ISUP-2 and ISUP-1 patients on AS. Conclusion: AS for carefully selected men with favourable risk ISUP-2 disease appears safe, with similar oncologic outcomes to men with ISUP-1 disease. Level of evidence: Level 2b