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1.
Nat Genet ; 50(7): 928-936, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29892016

RESUMO

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.


Assuntos
Neoplasias da Próstata/genética , Estudos de Casos e Controles , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Risco
4.
BMJ ; 360: j5757, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29321194

RESUMO

OBJECTIVES: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. DESIGN: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. SETTING: Multiple institutions that were members of international PRACTICAL consortium. PARTICIPANTS: All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. MAIN OUTCOME MEASURES: Prediction with hazard score of age of onset of aggressive cancer in validation set. RESULTS: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. CONCLUSIONS: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.


Assuntos
Detecção Precoce de Câncer/métodos , Calicreínas/análise , Polimorfismo de Nucleotídeo Único/genética , Antígeno Prostático Específico/análise , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Idade de Início , Idoso , Estudos de Coortes , Intervalo Livre de Doença , Grupo com Ancestrais do Continente Europeu/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Valor Preditivo dos Testes , Neoplasias da Próstata/diagnóstico , Medição de Risco , Análise de Sobrevida
5.
Int J Cancer ; 140(1): 75-85, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27643404

RESUMO

Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Aldeído Desidrogenase/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Retinal Desidrogenase/genética , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/efeitos adversos , Aldeído-Desidrogenase Mitocondrial , Estudos de Casos e Controles , Progressão da Doença , Humanos , Incidência , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/mortalidade , Análise de Regressão , Análise de Sobrevida
6.
Hum Mol Genet ; 25(24): 5490-5499, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27798103

RESUMO

Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.


Assuntos
Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/genética , Serina Endopeptidases/genética , Regulação Neoplásica da Expressão Gênica/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hibridização in Situ Fluorescente , Masculino , Neoplasias da Próstata/patologia , Locos de Características Quantitativas/genética , Regulador Transcricional ERG/genética
7.
Br J Cancer ; 115(5): 624-31, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27490808

RESUMO

BACKGROUND: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk. METHODS: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally-weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression. RESULTS: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA=0.95, 95%CI=0.92, 0.98) and α-linolenic acids (ORALA=0.96, 95%CI=0.93, 0.98), among men <62 years; whereas increased risk was found among men ⩾62 years for LA (ORLA=1.04, 95%CI=1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA=1.05, 95%CI=1.02, 1.08; OREPA=1.04, 95%CI=1.01, 1.06; ORDPA=1.05, 95%CI=1.02, 1.08). CONCLUSION: Results from this study suggest that circulating ω-3 and ω-6 PUFAs may have a different role in the aetiology of early- and late-onset prostate cancer.


Assuntos
Ácidos Graxos Insaturados/metabolismo , Neoplasias da Próstata/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Fatores de Risco
8.
Cancer Epidemiol Biomarkers Prev ; 25(12): 1619-1624, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27539266

RESUMO

BACKGROUND: We have developed a genome-wide association study analysis method called DEPTH (DEPendency of association on the number of Top Hits) to identify genomic regions potentially associated with disease by considering overlapping groups of contiguous markers (e.g., SNPs) across the genome. DEPTH is a machine learning algorithm for feature ranking of ultra-high dimensional datasets, built from well-established statistical tools such as bootstrapping, penalized regression, and decision trees. Unlike marginal regression, which considers each SNP individually, the key idea behind DEPTH is to rank groups of SNPs in terms of their joint strength of association with the outcome. Our aim was to compare the performance of DEPTH with that of standard logistic regression analysis. METHODS: We selected 1,854 prostate cancer cases and 1,894 controls from the UK for whom 541,129 SNPs were measured using the Illumina Infinium HumanHap550 array. Confirmation was sought using 4,152 cases and 2,874 controls, ascertained from the UK and Australia, for whom 211,155 SNPs were measured using the iCOGS Illumina Infinium array. RESULTS: From the DEPTH analysis, we identified 14 regions associated with prostate cancer risk that had been reported previously, five of which would not have been identified by conventional logistic regression. We also identified 112 novel putative susceptibility regions. CONCLUSIONS: DEPTH can reveal new risk-associated regions that would not have been identified using a conventional logistic regression analysis of individual SNPs. IMPACT: This study demonstrates that the DEPTH algorithm could identify additional genetic susceptibility regions that merit further investigation. Cancer Epidemiol Biomarkers Prev; 25(12); 1619-24. ©2016 AACR.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Aprendizado de Máquina , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Austrália , Humanos , Masculino , Pessoa de Meia-Idade , Reino Unido
9.
Sci Transl Med ; 8(341): 341ra76, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27252175

RESUMO

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.


Assuntos
Doença das Coronárias/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Alelos , Diabetes Mellitus Tipo 2/genética , Dipeptidil Peptidase 4/genética , Genótipo , Humanos , Obesidade/genética , Receptor CB2 de Canabinoide/genética , Receptor 5-HT2C de Serotonina/genética , Receptores de Somatostatina/genética , Transportador 1 de Glucose-Sódio/genética
10.
Int J Cancer ; 139(7): 1520-33, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27225428

RESUMO

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.


Assuntos
Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Somatomedinas/genética , Somatomedinas/metabolismo , Idoso , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Reino Unido/epidemiologia
11.
Nat Commun ; 7: 10979, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27052111

RESUMO

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.


Assuntos
Afro-Americanos , Epigênese Genética , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Padrões de Herança , Neoplasias da Próstata/genética , Acetilação , Atlas como Assunto , Linhagem Celular Tumoral , Loci Gênicos , Estudo de Associação Genômica Ampla , Histonas/genética , Histonas/metabolismo , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia
12.
BMC Med ; 14: 66, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-27044414

RESUMO

BACKGROUND: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach. METHODS: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample. RESULTS: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade. CONCLUSIONS: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.


Assuntos
Neoplasias da Próstata , Maturidade Sexual/genética , Adolescente , Idade de Início , Idoso , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/fisiopatologia , Puberdade/fisiologia , Distribuição Aleatória , Análise de Regressão , Fatores de Risco , Análise de Sobrevida , Reino Unido/epidemiologia
13.
Br J Cancer ; 114(8): 945-52, 2016 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-26964030

RESUMO

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.


Assuntos
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 , Risco
14.
Oncotarget ; 7(16): 21393-403, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-26881390

RESUMO

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Grupo com Ancestrais do Continente Asiático/genética , China , Cromossomos Humanos Par 8/genética , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Loci Gênicos/genética , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Neoplasias da Próstata/etnologia , Fatores de Risco
15.
Cell Cycle ; 15(1): 22-4, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26771711

RESUMO

Genome-wide association studies (GWAS) have revealed numerous genomic 'hits' associated with complex phenotypes. In most cases these hits, along with surrogate genetic variation as measure by numerous single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium, are not in coding genes making assignment of functionality or causality intractable. Here we propose that fine-mapping along with the matching of risk SNPs at chromatin biofeatures lessen this complexity by reducing the number of candidate functional/causal SNPs. For example, we show here that only on average 2 SNPs per prostate cancer risk locus are likely candidates for functionality/causality; we further propose that this manageable number should be taken forward in mechanistic studies. The candidate SNPs can be looked up for each prostate cancer risk region in 2 recent publications in 2015 (1,2) from our groups.


Assuntos
Predisposição Genética para Doença/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Desequilíbrio de Ligação/fisiologia , Animais , Estudo de Associação Genômica Ampla/tendências , Humanos , Polimorfismo de Nucleotídeo Único/fisiologia
16.
Cancer Causes Control ; 26(11): 1603-16, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26387087

RESUMO

BACKGROUND: Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality. METHODS: We conducted a case-control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man's number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies. RESULTS: The genetic risk scores explained 6.31 and 1.46% of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95% CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95% CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03). CONCLUSIONS: We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication.


Assuntos
Estatura/genética , Índice de Massa Corporal , Fenótipo , Neoplasias da Próstata/epidemiologia , Adiposidade/genética , Idoso , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Variação Genética , Genótipo , Humanos , Incidência , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Obesidade/complicações , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Fatores de Risco
17.
Cancer Epidemiol Biomarkers Prev ; 24(11): 1796-800, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26307654

RESUMO

BACKGROUND: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. METHODS: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). RESULTS: We observed no significant association between genetic variants and prostate cancer survival. CONCLUSIONS: Common genetic variants with large impact on prostate cancer survival were not observed in this study. IMPACT: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes.


Assuntos
Neoplasias da Próstata/mortalidade , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Análise de Sobrevida
18.
J Natl Cancer Inst ; 107(11)2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26319099

RESUMO

BACKGROUND: Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted. METHODS: We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided. RESULTS: We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003). CONCLUSIONS: Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Inflamação/genética , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Proteínas/genética , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal , Neoplasias da Mama/metabolismo , Neoplasias Colorretais/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pulmonares/metabolismo , Masculino , Neoplasias Ovarianas/metabolismo , Neoplasias da Próstata/metabolismo
19.
Hum Mol Genet ; 24(19): 5603-18, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26162851

RESUMO

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Hispano-Americanos/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Mapeamento Cromossômico/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Anotação de Sequência Molecular , Neoplasias da Próstata/etnologia , Locos de Características Quantitativas
20.
Nat Genet ; 46(10): 1103-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25217961

RESUMO

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Medição de Risco , Fatores de Risco
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