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1.
J Natl Cancer Inst ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31917448

RESUMO

BACKGROUND: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study (TWAS) in Europeans using three approaches, FUSION, MetaXcan and SMulTiXcan. We integrated GWAS summary statistics from 9,040 pancreatic cancer cases and 12,496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics, LTG (n = 95) and Genotype-Tissue Expression, GTEx v7 (n = 174) datasets), and data from 48 different tissues (GTEx v7, n = 74-421 samples). RESULTS: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (FDR < 0.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12:, PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at 6 known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci, and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1 and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

2.
Blood Adv ; 4(1): 181-190, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31935283

RESUMO

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

3.
Int J Cancer ; 146(3): 861-873, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31037736

RESUMO

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.


Assuntos
Neoplasias Colorretais/etiologia , Etanol/efeitos adversos , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Estudos de Casos e Controles , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de Risco
4.
Cancer Epidemiol ; 63: 101619, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639607

RESUMO

BACKGROUND: Prostate cancer is ubiquitous in older men; differential screening patterns and variations in biopsy recommendations and acceptance will affect which man is diagnosed and, therefore, evaluation of cancer risk factors. We describe a statistical method to reduce prostate cancer detection bias among African American (n = 3398) and Non-Hispanic White men (n = 22,673) who participated in the Selenium and Vitamin E Cancer Prevention trial (SELECT) and revisit a previously reported association between race, obesity and prostate cancer risk. METHODS: For men with screening values suggesting prostate cancer but in whom biopsy was not performed, the Prostate Cancer Prevention Trial Risk Calculator was used to estimate probability of prostate cancer. Associations of body mass index (BMI) and race with incident prostate cancer were compared for observed versus imputation-enhanced outcomes using incident density ratios. RESULTS: Accounting for differential biopsy assessment, the previously reported positive linear trend between BMI and prostate cancer in African American men was not observed; no BMI association was found among Non-Hispanic White men. CONCLUSIONS: Differential disease classification among men who may be recommended to undergo and then consider whether to accept a prostate biopsy leads to inaccurate identification of prostate cancer risk factors. Imputing a man's prostate cancer status reduces detection bias. Covariate adjustment does not address the problem of outcome misclassification. Cohorts evaluating incident prostate cancer should collect longitudinal screening and biopsy data to adjust for this potential bias.

8.
Cancer Prev Res (Phila) ; 12(2): 113-120, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30538099

RESUMO

In the Prostate Cancer Prevention Trial (PCPT), genotypes that may modify the effect of finasteride on the risk of prostate cancer have not been identified. Germline genetic data from 1,157 prostate cancer cases in PCPT were analyzed by case-only methods. Genotypes included 357 SNPs from 83 candidate genes in androgen metabolism, inflammation, circadian rhythm, and other pathways. Univariate case-only analysis was conducted to evaluate whether individual SNPs modified the finasteride effect on the risk of high-grade and low-grade prostate cancer. Case-only classification trees and random forests, which are powerful machine learning methods with resampling-based controls for model complexity, were employed to identify a predictive signature for genotype-specific treatment effects. Accounting for multiple testing, a single SNP in SRD5A1 gene (rs472402) significantly modified the finasteride effect on high-grade prostate cancer (Gleason score > 6) in PCPT (family-wise error rate < 0.05). Men carrying GG genotype at this locus had a 55% reduction of the risk in developing high-grade cancer when assigned to finasteride (RR = 0.45; 95% confidence interval, 0.27-0.75). Additional effect-modifying SNPs with moderate statistical significance were identified by case-only trees and random forests. A prediction model built by the case-only random forest method with 28 selected SNPs classified 37% of PCPT men to have reduced risk of high-grade prostate cancer when taking finasteride, while the others have increased risk. In conclusion, case-only methods identified SNPs that modified the effect of finasteride on the risk of high-grade prostate cancer and predicted a subgroup of men who had reduced cancer risk by finasteride.

9.
Gut ; 68(6): 960-968, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30121626

RESUMO

OBJECTIVE: Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk. DESIGN: This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy. RESULTS: Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk. CONCLUSION: This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer , Neoplasias Esofágicas/diagnóstico , Mediadores da Inflamação/sangue , Adenocarcinoma/epidemiologia , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Idoso , Índice de Massa Corporal , Consenso , Estudos Transversais , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirurgia , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fumar/epidemiologia
10.
J Natl Cancer Inst ; 111(6): 557-567, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30541042

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. METHODS: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. RESULTS: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. CONCLUSION: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

11.
Cancer Epidemiol ; 55: 117-122, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29936140

RESUMO

BACKGROUND: The cancer research groups of the National Cancer Institute's National Clinical Trials Network have a history of successful conduct of large randomized phase III trials of chemoprevention for cancer. An important question for funding agencies is whether the conduct of large chemoprevention trials provides strong scientific return on investment. METHODS: We evaluated the scientific impact of four large chemoprevention trials - two for breast cancer and two for prostate cancer - using citation analysis, a bibliometric technique. The results were compared to the scientific impact of a series of treatment trials conducted over the same 20-year time period (1991-2010, inclusive). Average annual citation counts were compared using t-tests. Scientific impact was also assessed relative to trial costs. RESULTS: Twenty-seven treatment trials with 17,208 patients and four chemoprevention trials with 87,550 patients were examined. The mean annual citation rate for primary articles was higher for chemoprevention trials compared to treatment trials (188.1 vs. 40.4, p = .001). For both primary and secondary article publications, mean annual citations for articles associated with chemoprevention trials were also higher (483.9 vs. 69.0, p = .0003). Large chemoprevention trials were estimated to provide 50% more total citations from primary and secondary articles on a cost-adjusted basis. CONCLUSION: Based on these criteria, the scientific impact of large phase III cancer chemoprevention trials was very high in absolute terms, and as good as or better than that of treatment trials after accounting for expenditure. For appropriate scientific questions, large chemoprevention trials provide a good scientific return on investment for federal funding agencies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/prevenção & controle , Ensaios Clínicos Fase III como Assunto , Publicações Periódicas como Assunto/estatística & dados numéricos , Neoplasias da Próstata/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Pesquisa Biomédica , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Feminino , Humanos , Masculino , National Cancer Institute (U.S.) , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Taxa de Sobrevida , Resultado do Tratamento , Estados Unidos
12.
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
13.
J Natl Cancer Inst ; 110(11): 1208-1215, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29534197

RESUMO

Background: Investigators have used administrative claims to better understand cancer outcomes when a research question cannot feasibly be examined within a study. The Prostate Cancer Prevention Trial (PCPT) showed that seven years of finasteride reduced prostate cancer (PC) risk by 25% in men age 55 years or older. However, it was unclear whether the observed reduction in PC for finasteride participants would be maintained after finasteride discontinuation. Methods: We examined PC diagnoses identified by PCPT study records and Medicare claims (finasteride = 9423, placebo = 9457). A Medicare-defined PC diagnosis algorithm was defined using diagnosis and procedure codes. Multivariable Cox regression was used to examine time to PC within prespecified follow-up windows (<6.5, 6.5-7.5, and >7.5 years) using time-dependent covariates interacting with intervention assignment to account for the PCPT protocol-specified end-of-study biopsy at seven years. All statistical tests were two-sided. Results: Median follow-up using the linked database was 16 years. Overall, finasteride arm participants had a 21.1% decrease in the hazard ratio of PC (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.74 to 0.84, P < .001). The beneficial effect of finasteride in reducing the hazard ratio of PC was most pronounced in the first 7.5 years (HR = 0.71, 95% CI = 0.66 to 0.77, P < .001), consistent with the original study findings; after 7.5 years, there was no increased risk of PC for finasteride arm participants (HR = 1.10, 95% CI = 0.96 to 1.26, P = .18). Conclusions: Finasteride provides a substantial reduction in PC through 16 years of follow-up. There was no strong evidence that the benefit of finasteride diminished after the end-of-study follow-up. Utilizing Medicare claims to augment PCPT follow-up illustrates how the novel use of secondary data sources can enhance the ability to detect long-term outcomes from prospective studies.


Assuntos
Inibidores de 5-alfa Redutase/efeitos adversos , Finasterida/efeitos adversos , Medicare , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/prevenção & controle , Inibidores de 5-alfa Redutase/administração & dosagem , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , Finasterida/administração & dosagem , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Vigilância em Saúde Pública , Estados Unidos/epidemiologia
14.
Nat Commun ; 9(1): 556, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29422604

RESUMO

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.


Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Bases de Dados Genéticas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fator 1-beta Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Proteínas Repressoras/genética , Tensinas/genética
15.
Mol Carcinog ; 57(3): 462-466, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29318656

RESUMO

Circadian genes have been considered as a possible biological mechanism for the observed relationship between circadian rhythm disruptions and increased risk of hormone-related cancers. In the current study, we investigated the relationship between circadian gene variants and prostate cancer risk and whether reducing bioavailable testosterone modifies the circadian genes-prostate cancer relationship. We conducted a nested case-control study among Caucasian men in the Prostate Cancer Prevention Trial (PCPT), a randomized placebo-controlled clinical trial to assess if finasteride (an androgen bioactivation inhibitor) could prevent prostate cancer. We evaluated the associations between 240 circadian gene variations and prostate cancer risk among 1092 biopsy-confirmed prostate cancer cases and 1089 biopsy-negative controls in the study (642 cases and 667 controls from the placebo group; 450 cases and 422 controls from the finasteride group), stratified by treatment group. Among men in the finasteride group, there were suggestive associations between NPAS2 variants and total prostate cancer risk, with one SNP remaining statistically significant after Bonferroni correction (rs746924, odds ratio [OR] = 1.5, P = 9.6 × 10-5 ). However, we found little evidence of increased prostate cancer risk (overall or by low/high grade) associated with circadian gene variations in men of the placebo group, suggesting potential modification of genetic effects by treatment. We did not find strong evidence that circadian gene variants influenced prostate cancer risk in men who were not on finasteride treatment. There were suggestive associations between NPAS2 variants and prostate cancer risk among men using finasteride, which warrants further investigations.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Finasterida/uso terapêutico , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Neoplasias da Próstata/prevenção & controle , Idoso , Estudos de Casos e Controles , Relógios Circadianos , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/efeitos dos fármacos , Próstata/enzimologia , Próstata/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/epidemiologia , Fatores de Risco
16.
Carcinogenesis ; 39(2): 125-133, 2018 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-29228205

RESUMO

Substantial preclinical data suggest estrogen's carcinogenic role in prostate cancer development; however, epidemiological evidence based on circulating estrogen levels is largely null. Compared with circulating estrogen, the intraprostatic estrogen milieu may play a more important role in prostate carcinogenesis. Using a nested case-control design in the Prostate Cancer Prevention Trial (PCPT), we examined associations of genetic variants of genes that are involved in estrogen synthesis, metabolism and function with prostate cancer risk. A total of 25 potentially functional single nucleotide polymorphisms (SNPs) in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined in whites only. Controls (n = 1380) were frequency matched to cases on age, PCPT treatment arm, and family history (n = 1506). Logistic regression models adjusted for age and family history were used to estimate odds ratios (OR) and 95% confidence intervals (CI) separately in the placebo and finasteride arms. SNPs associated with prostate cancer risk differed by treatment arm. The associations appeared to be modified by circulating estrogen and androgen levels. CYP19A1 was the only gene harboring SNPs that were significantly associated with risk in both the placebo and finasteride arms. Haplotype analysis with all three CYP19A1 SNPs genotyped (rs700518, rs2445765, rs700519) showed that risk-allele haplotypes are associated with the increased prostate cancer risk in both arms when comparing with the non-risk allele haplotype. In conclusion, associations between SNPs in estrogen-related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment.


Assuntos
Aromatase/genética , Estrogênios/metabolismo , Predisposição Genética para Doença/genética , Neoplasias da Próstata/genética , Inibidores de 5-alfa Redutase/uso terapêutico , Idoso , Estudos de Casos e Controles , Finasterida/uso terapêutico , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/prevenção & controle
17.
PLoS One ; 12(12): e0187741, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29281666

RESUMO

INTRODUCTION: Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin. METHODS: Statistical analyses of individual participant data from 12,330 male controls aged 25-85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates. RESULTS: Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones. CONCLUSION: Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption.


Assuntos
Antropometria , Comportamento , Conjuntos de Dados como Assunto , Hormônios Esteroides Gonadais/sangue , Classe Social , Adulto , Humanos , Masculino , Adulto Jovem
18.
J Natl Cancer Inst ; 109(8)2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29117387

RESUMO

Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Loci Gênicos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2/genética , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 22 , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Masculino
19.
Cancer Epidemiol Biomarkers Prev ; 26(10): 1549-1557, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28754796

RESUMO

Background: We leveraged two trials to test the hypothesis of an inflammation-prostate cancer link prospectively in men without indication for biopsy.Methods: Prostate Cancer Prevention Trial (PCPT) participants who had an end-of-study biopsy performed per protocol that was negative for cancer and who subsequently enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) were eligible. We selected all 100 cases and sampled 200 frequency-matched controls and used PCPT end-of-study biopsies as "baseline." Five men with PSA > 4 ng/mL at end-of-study biopsy were excluded. Tissue was located for 92 cases and 193 controls. We visually assessed inflammation in benign tissue. We estimated ORs and 95% confidence intervals (CI) using logistic regression adjusting for age and race.Results: Mean time between biopsy and diagnosis was 5.9 years. In men previously in the PCPT placebo arm, 78.1% of cases (N = 41) and 68.2% of controls (N = 85) had at least one baseline biopsy core (∼5 evaluated per man) with inflammation. The odds of prostate cancer (N = 41 cases) appeared to increase with increasing mean percentage of tissue area with inflammation, a trend that was statistically significant for Gleason sum <4+3 disease (N = 31 cases; vs. 0%, >0-<1.8% OR = 1.70, 1.8-<5.0% OR = 2.39, ≥5% OR = 3.31, Ptrend = 0.047). In men previously in the finasteride arm, prevalence of inflammation did not differ between cases (76.5%; N = 51) and controls (75.0%; N = 108).Conclusions: Benign tissue inflammation was positively associated with prostate cancer.Impact: This first prospective study of men without biopsy indication supports the hypothesis that inflammation influences prostate cancer development. Cancer Epidemiol Biomarkers Prev; 26(10); 1549-57. ©2017 AACR.


Assuntos
Próstata/patologia , Neoplasias da Próstata/etiologia , Idoso , Doença Crônica , Estudos de Coortes , Humanos , Inflamação/patologia , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Neoplasias da Próstata/patologia , Risco
20.
PLoS Genet ; 13(4): e1006719, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28430825

RESUMO

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.


Assuntos
Adiposidade/genética , Obesidade/genética , Serina Endopeptidases/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Grupo com Ancestrais do Continente Africano/genética , Antropometria , Índice de Massa Corporal , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Relação Cintura-Quadril
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