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Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.
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Predisposição Genética para Doença , Neoplasias da Próstata , Humanos , Masculino , População Negra/genética , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Neoplasias da Próstata/genética , Fatores de Risco , População Branca/genéticaRESUMO
Prostate cancer is the second most common solid tumour in men worldwide and it is also the most common cancer affecting men of African descent. Prostate cancer incidence and mortality vary across regions and populations. Some of this is explained by a large heritable component of this disease. It has been established that men of African and African Caribbean ethnicity are predisposed to prostate cancer (PrCa) that can have an earlier onset and a more aggressive course, thereby leading to poorer outcomes for patients in this group. Literature searches were carried out using the PubMed, EMBASE and Cochrane Library databases to identify studies associated with PrCa risk and its association with ancestry, screening and management of PrCa. In order to be included, studies were required to be published in English in full-text form. An attractive approach is to identify high-risk groups and develop a targeted screening programme for them as the benefits of population-wide screening in PrCa using prostate-specific antigen (PSA) testing in general population screening have shown evidence of benefit; however, the harms are considered to weigh heavier because screening using PSA testing can lead to over-diagnosis and over-treatment. The aim of targeted screening of higher-risk groups identified by genetic risk stratification is to reduce over-diagnosis and treat those who are most likely to benefit.
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Antígeno Prostático Específico , Neoplasias da Próstata , Humanos , Masculino , Detecção Precoce de Câncer , Programas de Rastreamento , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genéticaRESUMO
OBJECTIVES: To assess the feasibility and uptake of a community-based prostate cancer (PCa) screening programme selecting men according to their genetic risk of PCa. To assess the uptake of PCa screening investigations by men invited for screening. The uptake of the pilot study would guide the opening of the larger BARCODE1 study recruiting 5000 men. SUBJECTS AND METHODS: Healthy males aged 55-69 years were invited to participate via their general practitioners (GPs). Saliva samples were collected via mailed collection kits. After DNA extraction, genotyping was conducted using a study specific assay. Genetic risk was based on genotyping 130 germline PCa risk single nucleotide polymorphisms (SNPs). A polygenic risk score (PRS) was calculated for each participant using the sum of weighted alleles for 130 SNPs. Study participants with a PRS lying above the 90th centile value were invited for PCa screening by prostate magnetic resonance imaging (MRI) and biopsy. RESULTS: Invitation letters were sent to 1434 men. The overall study uptake was 26% (375/1436) and 87% of responders were eligible for study entry. DNA genotyping data were available for 297 men and 25 were invited for screening. After exclusions due to medical comorbidity/invitations declined, 18 of 25 men (72%) underwent MRI and biopsy of the prostate. There were seven diagnoses of PCa (38.9%). All cancers were low-risk and were managed with active surveillance. CONCLUSION: The BARCODE1 Pilot has shown this community study in the UK to be feasible, with an overall uptake of 26%. The main BARCODE1 study is now open and will recruit 5000 men. The results of BARCODE1 will be important in defining the role of genetic profiling in targeted PCa population screening. Patient Summary What is the paper about? Very few prostate cancer screening programmes currently exist anywhere in the world. Our pilot study investigated if men in the UK would find it acceptable to have a genetic test based on a saliva sample to examine their risk of prostate cancer development. This test would guide whether men are offered prostate cancer screening tests. What does it mean for patients? We found that the study design was acceptable: 26% of men invited to take part agreed to have the test. The majority of men who were found to have an increased genetic risk of prostate cancer underwent further tests offered (prostate MRI scan and biopsy). We have now expanded the study to enrol 5000 men. The BARCODE1 study will be important in examining whether this approach could be used for large-scale population prostate cancer screening.
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Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata , Detecção Precoce de Câncer/métodos , Estudos de Viabilidade , Células Germinativas/patologia , Humanos , Masculino , Projetos Piloto , Polimorfismo de Nucleotídeo Único/genética , Antígeno Prostático Específico/genética , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
This article was originally published under the standard License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly.
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BACKGROUND: Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. METHODS: We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. RESULTS: Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. CONCLUSIONS: Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application.
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Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA2/genética , Proteínas de Ciclo Celular/genética , Proteínas Nucleares/genética , Neoplasias da Próstata/genética , Idoso , Reparo do DNA/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/patologia , Sequenciamento do ExomaRESUMO
This corrects the article DOI: 10.1038/bjc.2016.50.
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The U.S. Office of Adolescent Health and the Centers for Disease Control continue to promote a community mobilization model in support of teen pregnancy prevention in new grant initiatives. The most recent federal grant program-the "Communitywide Initiatives (2010-2015)" grant-promoted pregnancy prevention using three teams within the nine targeted communities to promote evidence-based sexuality education programs and enhanced access to contraceptive services among adolescents. The "lessons" reported in this article are compiled from three key informant interviews conducted with all project coordinators over the course of the 5 years (2010-2015) that this grant was implemented. Both successes and challenges to community mobilization in support of teen pregnancy prevention are presented and discussed.
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Redes Comunitárias , Gravidez na Adolescência/prevenção & controle , Adolescente , Feminino , Promoção da Saúde , Humanos , Entrevistas como Assunto , Gravidez , Educação SexualRESUMO
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain â¼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.
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Mapeamento Cromossômico/métodos , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , População Branca/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , MasculinoRESUMO
UNLABELLED: : In this article, we present LocusExplorer, a data visualization and exploration tool for genetic association data. LocusExplorer is written in R using the Shiny library, providing access to powerful R-based functions through a simple user interface. LocusExplorer allows users to simultaneously display genetic, statistical and biological data for humans in a single image and allows dynamic zooming and customization of the plot features. Publication quality plots may then be produced in a variety of file formats. AVAILABILITY AND IMPLEMENTATION: LocusExplorer is open source and runs through R and a web browser. It is available at www.oncogenetics.icr.ac.uk/LocusExplorer/ or can be installed locally and the source code accessed from https://github.com/oncogenetics/LocusExplorer CONTACT: tokhir.dadaev@icr.ac.uk.
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Software , Genética Médica , Humanos , Linguagens de Programação , NavegadorRESUMO
The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, Pâ=â2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
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Predisposição Genética para Doença , Variação Genética , Proteínas de Homeodomínio/genética , Neoplasias da Próstata/genética , Alelos , Cromossomos Humanos Par 17/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Fatores de RiscoRESUMO
BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.
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Reparo do DNA/genética , DNA/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Proteína BRCA1/genética , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Genes BRCA2/fisiologia , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Estudos Prospectivos , RiscoRESUMO
Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.
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Cromossomos Humanos Par 5/genética , Predisposição Genética para Doença , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Telomerase/genética , Adulto , Estudos de Casos e Controles , Mapeamento Cromossômico , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Telomerase/metabolismoRESUMO
BACKGROUND: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes. OBJECTIVE: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS). DESIGN, SETTING, AND PARTICIPANTS: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival. RESULTS AND LIMITATIONS: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10-16) than noncarriers. CONCLUSIONS: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations. PATIENT SUMMARY: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa.
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Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Próstata/patologia , Genes BRCA2 , MutaçãoRESUMO
OBJECTIVES: To explore the potential prognostic role of family history (FH) of prostate cancer and prostate cancer risk single nucleotide polymorphisms (SNPs) in patients undergoing active surveillance (AS) for prostate cancer. This is the first study to date, which has investigated the potential prognostic role of SNP profiles in an AS cohort PATIENTS AND METHODS: FH data were collected from patients in the Royal Marsden Hospital AS study. In all, 39 prostate cancer-risk SNPs identified from published genome wide association studies (GWAS) were genotyped using the Sequenom Platform and TaqMan™ assays from available DNA. The cumulative genetic-risk scores for each patient were then calculated using the weighted effect estimated from previous GWAS (log-additive model). FH status and the genetic-risk scores were assessed against adverse outcomes in AS, time to treatment and adverse histology on repeat biopsy, using univariable and multivariable Cox regression models to address time to treatment; and binary logistic regression to address biopsy upgrade. RESULTS: Of 471 patients, 55 (13.6%) had adverse histology on repeat biopsies and 145 (30.8%) had deferred treatment. On univariate analysis, there was no significant relationship between FH of prostate cancer in any degree of relation, and adverse histology or time to treatment. For risk score analyses, 386 patients' DNA was studied; and there was also no relationship found between the calculated genetic risk scores and adverse histology or time to treatment (P = 0.573 and P = 0.965, respectively). The retrospective study design and the few events were the main limitation of the study. CONCLUSIONS: There is currently insufficient data to support the use of FH status or prostate cancer SNP profile risk scores as prognostic factors in AS and these should not be used to influence management decisions. As more genetic variants are discovered this may change and should be reassessed in multicentre AS cohorts.
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Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Idoso , Família , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/epidemiologia , Estudos Retrospectivos , Medição de Risco , Vigilância de Evento Sentinela , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Genetic factors play an important role in prostate cancer (PCa) susceptibility. OBJECTIVE: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. RESULTS AND LIMITATIONS: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4). CONCLUSIONS: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. PATIENT SUMMARY: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.
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Predisposição Genética para Doença , Neoplasias da Próstata , Masculino , Humanos , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/genética , Neoplasias da Próstata/epidemiologia , Fatores de Risco , População Negra/genéticaRESUMO
The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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Predisposição Genética para Doença , Neoplasias da Próstata , Humanos , Masculino , População Negra/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Fatores de Risco , População Branca/genética , Povo Asiático/genéticaRESUMO
Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.
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BACKGROUND: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. OBJECTIVE: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic factors associated with such progression. DESIGN, SETTING, AND PARTICIPANTS: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG) consortium from the UK, Canada, Germany, Australia, and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA) dataset. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A total of 15,822 rare (MAF <1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene sets. Models were tested for robustness using bootstrap resampling. RESULTS AND LIMITATIONS: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in "Hallmark" gene sets were consistently associated with altered time to BCR. Three gene sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response, and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher-grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB, and Hypoxia, the latter of which was validated in the independent TCGA dataset. CONCLUSIONS: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management. PATIENT SUMMARY: Prostate cancer patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify patients who might need additional treatments earlier.
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Fosfatidilinositol 3-Quinases , Neoplasias da Próstata , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Fosfatidilinositol 3-Quinases/genética , Prostatectomia , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/terapia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Serina-Treonina Quinases TORRESUMO
Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine.
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Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.