Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 303
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-30352818

RESUMO

BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

2.
Diabetes ; 66(11): 2903-2914, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28838971

RESUMO

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.


Assuntos
Diabetes Mellitus Tipo 2/genética , Fator de Crescimento Insulin-Like II/metabolismo , Sítios de Splice de RNA/genética , Tecido Adiposo , Linhagem Celular , Grupo com Ancestrais do Continente Europeu , Regulação da Expressão Gênica/fisiologia , Variação Genética , Genótipo , Humanos , Fator de Crescimento Insulin-Like II/genética , Fígado , Americanos Mexicanos/genética , México , Isoformas de Proteínas , Células-Tronco
3.
Breast Cancer Res ; 18(1): 109, 2016 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-27814745

RESUMO

BACKGROUND: Although genome-wide association studies (GWASs) have identified thousands of disease susceptibility regions, the underlying causal mechanism in these regions is not fully known. It is likely that the GWAS signal originates from one or many as yet unidentified causal variants. METHODS: Using next-generation sequencing, we characterized 12 breast cancer susceptibility regions identified by GWASs in 2288 breast cancer cases and 2323 controls across four populations of African American, European, Japanese, and Hispanic ancestry. RESULTS: After genotype calling and quality control, we identified 137,530 single-nucleotide variants (SNVs); of those, 87.2 % had a minor allele frequency (MAF) <0.005. For SNVs with MAF >0.005, we calculated the smallest number of SNVs needed to obtain a posterior probability set (PPS) such that there is 90 % probability that the causal SNV is included. We found that the PPS for two regions, 2q35 and 11q13, contained less than 5 % of the original SNVs, dramatically decreasing the number of potentially causal SNVs. However, we did not find strong evidence supporting a causal role for any individual SNV. In addition, there were no significant gene-based rare SNV associations after correcting for multiple testing. CONCLUSIONS: This study illustrates some of the challenges faced in fine-mapping studies in the post-GWAS era, most importantly the large sample sizes needed to identify rare-variant associations or to distinguish the effects of strongly correlated common SNVs.


Assuntos
Neoplasias da Mama/genética , Grupos Étnicos/genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Enfermeiras e Enfermeiros , Fases de Leitura Aberta , Polimorfismo de Nucleotídeo Único
4.
J Natl Cancer Inst ; 108(11)2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27385803

RESUMO

BACKGROUND: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. METHODS: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. RESULTS: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, Pheterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, Ptrend < .001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, Pheterogeneity = .08). CONCLUSIONS: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.


Assuntos
Unhas/química , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Selênio/análise , Idoso , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/etiologia , Fatores de Proteção , Medição de Risco , Selênio/sangue , Dedos do Pé
5.
Int J Cancer ; 139(12): 2655-2670, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27459707

RESUMO

Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.


Assuntos
Variação Genética , Neoplasias/epidemiologia , Neoplasias/genética , Homeostase do Telômero/genética , Telômero/genética , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Razão de Chances , Polimorfismo de Nucleotídeo Único , Risco , Telomerase/genética
6.
Lung Cancer ; 98: 33-42, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27393504

RESUMO

OBJECTIVES: Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping. MATERIALS AND METHODS: We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2. RESULTS AND CONCLUSION: In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.


Assuntos
Afro-Americanos/genética , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 5 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Locos de Características Quantitativas , Estudos de Casos e Controles , Humanos , Polimorfismo de Nucleotídeo Único , Vigilância da População
7.
Int J Epidemiol ; 45(3): 896-908, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27427428

RESUMO

BACKGROUND: Adiposity traits have been associated with risk of many cancers in observational studies, but whether these associations are causal is unclear. Mendelian randomization (MR) uses genetic predictors of risk factors as instrumental variables to eliminate reverse causation and reduce confounding bias. We performed MR analyses to assess the possible causal relationship of birthweight, childhood and adult body mass index (BMI), and waist-hip ratio (WHR) on the risks of breast, ovarian, prostate, colorectal and lung cancers. METHODS: We tested the association between genetic risk scores and each trait using summary statistics from published genome-wide association studies (GWAS) and from 51 537 cancer cases and 61 600 controls in the Genetic Associations and Mechanisms in Oncology (GAME-ON) Consortium. RESULTS: We found an inverse association between the genetic score for childhood BMI and risk of breast cancer [odds ratio (OR) = 0.71 per standard deviation (s.d.) increase in childhood BMI; 95% confidence interval (CI): 0.60, 0.80; P = 6.5 × 10(-5)). We also found the genetic score for adult BMI to be inversely associated with breast cancer risk (OR = 0.66 per s.d. increase in BMI; 95% CI: 0.57, 0.77; P = 2.5 × 10(-7)), and positively associated with ovarian cancer (OR = 1.35; 95% CI: 1.05, 1.72; P = 0.017), lung cancer (OR = 1.27; 95% CI: 1.09, 1.49; P = 2.9 × 10(-3)) and colorectal cancer (OR = 1.39; 95% CI: 1.06, 1.82, P = 0.016). The inverse association between genetically predicted adult BMI and breast cancer risk remained even after adjusting for directional pleiotropy via MR-Egger regression. CONCLUSIONS: Findings from this study provide additional understandings of the complex relationship between adiposity and cancer risks. Our results for breast and lung cancer are particularly interesting, given previous reports of effect heterogeneity by menopausal status and smoking status.


Assuntos
Adiposidade/genética , Índice de Massa Corporal , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Relação Cintura-Quadril , Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Análise da Randomização Mendeliana , Neoplasias/epidemiologia , Razão de Chances , Neoplasias Ovarianas/genética , Fenótipo , Neoplasias da Próstata/genética , Análise de Regressão , Fatores de Risco
8.
JAMA Oncol ; 2(10): 1295-1302, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27228256

RESUMO

Importance: An improved model for risk stratification can be useful for guiding public health strategies of breast cancer prevention. Objective: To evaluate combined risk stratification utility of common low penetrant single nucleotide polymorphisms (SNPs) and epidemiologic risk factors. Design, Setting, and Participants: Using a total of 17 171 cases and 19 862 controls sampled from the Breast and Prostate Cancer Cohort Consortium (BPC3) and 5879 women participating in the 2010 National Health Interview Survey, a model for predicting absolute risk of breast cancer was developed combining information on individual level data on epidemiologic risk factors and 24 genotyped SNPs from prospective cohort studies, published estimate of odds ratios for 68 additional SNPs, population incidence rate from the National Cancer Institute-Surveillance, Epidemiology, and End Results Program cancer registry and data on risk factor distribution from nationally representative health survey. The model is used to project the distribution of absolute risk for the population of white women in the United States after adjustment for competing cause of mortality. Exposures: Single nucleotide polymorphisms, family history, anthropometric factors, menstrual and/or reproductive factors, and lifestyle factors. Main Outcomes and Measures: Degree of stratification of absolute risk owing to nonmodifiable (SNPs, family history, height, and some components of menstrual and/or reproductive history) and modifiable factors (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared], menopausal hormone therapy [MHT], alcohol, and smoking). Results: The average absolute risk for a 30-year-old white woman in the United States developing invasive breast cancer by age 80 years is 11.3%. A model that includes all risk factors provided a range of average absolute risk from 4.4% to 23.5% for women in the bottom and top deciles of the risk distribution, respectively. For women who were at the lowest and highest deciles of nonmodifiable risks, the 5th and 95th percentile range of the risk distribution associated with 4 modifiable factors was 2.9% to 5.0% and 15.5% to 25.0%, respectively. For women in the highest decile of risk owing to nonmodifiable factors, those who had low BMI, did not drink or smoke, and did not use MHT had risks comparable to an average woman in the general population. Conclusions and Relevance: This model for absolute risk of breast cancer including SNPs can provide stratification for the population of white women in the United States. The model can also identify subsets of the population at an elevated risk that would benefit most from risk-reduction strategies based on altering modifiable factors. The effectiveness of this model for individual risk communication needs further investigation.


Assuntos
Neoplasias da Mama/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Comportamento de Redução do Risco , Estados Unidos/epidemiologia
9.
Int J Cancer ; 139(6): 1241-50, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27137137

RESUMO

In the Multiethnic Cohort Study, we previously reported that dietary fiber intake was inversely associated with colorectal cancer risk in men only. In women, the inverse relationship was weaker and appeared to be confounded by menopausal hormone therapy (MHT). We re-examined this observation with a greatly increased power. Using Cox proportional hazards models, we analyzed data from 187,674 participants with 4,692 cases identified during a mean follow-up period of 16 years. In multivariable-adjusted models, dietary fiber intake was inversely associated with colorectal cancer risk in both sexes: HR = 0.73, 95% CI: 0.61-0.89 for highest vs. lowest quintile, ptrend = 0.0020 in men and HR = 0.76, 95% CI: 0.62-0.91, ptrend = 0.0067 in women. Postmenopausal women who ever used MHT had a 19% lower risk of colorectal cancer (95% CI: 0.74-0.89) compared with MHT never users. In a joint analysis of dietary fiber and MHT, dietary fiber intake was associated with a lower colorectal cancer risk in MHT never users (HR = 0.75, 95% CI: 0.59-0.95, ptrend = 0.045), but did not appear to further decrease the colorectal cancer risk of MHT ever users (ptrend = 0.11). Our results support the overall protective roles of dietary fiber and MHT against colorectal cancer and suggest that dietary fiber may not lower risk further among women who ever used MHT. If confirmed, these results would suggest that MHT and dietary fiber may share overlapping mechanisms in protecting against colorectal cancer.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etiologia , Fibras na Dieta , Grupos Étnicos/estatística & dados numéricos , Terapia de Reposição Hormonal , Menopausa , Idoso , California/epidemiologia , Estudos de Coortes , Feminino , Hawaii/epidemiologia , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População , Fatores de Risco , Inquéritos e Questionários
10.
Hum Mol Genet ; 25(12): 2612-2620, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27008869

RESUMO

Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 -8) at 6p22.3 (rs1740828; P = 2.29 × 10 -8, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.


Assuntos
Neoplasias do Endométrio/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cromossomos Humanos Par 6/genética , Neoplasias do Endométrio/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
11.
Clin Gastroenterol Hepatol ; 14(2): 309-16, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26404865

RESUMO

BACKGROUND & AIMS: Obesity is associated with increased risk for hepatocellular carcinoma (HCC), but the risk associated with obesity may vary by sex or ethnicity. We examined whether the association of body mass index (BMI) with HCC incidence, as well as correlations of BMI with total, visceral, and hepatic adiposity, differs among ethnic groups. METHODS: We collected data from the Multiethnic Cohort Study, a population-based prospective cohort study of more than 215,000 men and women from Hawaii and California that was assembled from 1993 through 1996. After a median follow-up of 16.6 years, 482 incident HCC cases were identified among 168,476 participants. BMI and risk factor data were obtained from a baseline questionnaire. Cox regression analyses were used to calculate hazard ratios (HRs) and confidence intervals (CIs) for HCC associated with BMI. The black subjects in the Southern Community Cohort Study were included as a replication cohort. RESULTS: BMI was associated with HCC in men (HR per 5 kg/m(2) increase, 1.26; 95% CI, 1.12-1.42) but not in women (HR, 1.06; 95% CI, 0.90-1.25) (P(interaction) = .009). Although BMI was strongly associated with HCC in Japanese, white, and Latino men, there was no association in black men (P(interaction) = .002). Similarly, no association was found in the blacks who participated in the Southern Community Cohort Study. BMI correlated with total fat mass, measured by dual-energy x-ray absorptiometry, in men and women and in all ethnic groups (R ≥ 0.9). However, there was a lower correlation value for BMI and visceral or liver fat measured by abdominal magnetic resonance imaging in black men (R < 0.5) and in women (R < 0.8). CONCLUSIONS: On the basis of an analysis of data from the Multiethnic Cohort Study, the association between BMI and HCC differs between sexes and among ethnicities. The lack of association in black men warrants further investigation. Rather than studying markers of total adiposity, studies of obesity and HCC should move beyond BMI and use a better measure for fat-specific depots.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Grupos Étnicos , Obesidade/complicações , Idoso , Índice de Massa Corporal , California/epidemiologia , Estudos de Casos e Controles , Feminino , Hawaii/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais
12.
Carcinogenesis ; 37(1): 96-105, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26590902

RESUMO

Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000×) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73×10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64×10(-6)), rs112290073 (OR = 1.85, P = 1.27×10(-5)), rs138895564 (OR = 2.16, P = 2.06×10(-5); among young cases, OR = 3.77, P = 8.41×10(-4)). In addition, we found that rs139852726 (P = 1.44×10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84×10(-7)) and lung cancer (P = 2.37×10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.


Assuntos
Cromossomos Humanos Par 5 , Loci Gênicos , Neoplasias Pulmonares/genética , Estudos de Casos e Controles , Mapeamento Cromossômico/métodos , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem/métodos , Humanos , Masculino , Pessoa de Meia-Idade
13.
Hum Mol Genet ; 25(2): 371-81, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26604137

RESUMO

Prostate cancer is the most common non-skin cancer in males, with a ∼1.5-2-fold higher incidence in African American men when compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ∼33% of the familial risk. To explore the contribution of both rare and common variation in coding regions to prostate cancer risk, we sequenced the exomes of 2165 prostate cancer cases and 2034 controls of African ancestry at a mean coverage of 10.1×. We identified 395 220 coding variants down to 0.05% frequency [57% non-synonymous (NS), 42% synonymous and 1% gain or loss of stop codon or splice site variant] in 16 751 genes with the strongest associations observed in SPARCL1 on 4q22.1 (rs13051, Ala49Asp, OR = 0.78, P = 1.8 × 10(-6)) and PTPRR on 12q15 (rs73341069, Val239Ile, OR = 1.62, P = 2.5 × 10(-5)). In gene-level testing, the two most significant genes were C1orf100 (P = 2.2 × 10(-4)) and GORAB (P = 2.3 × 10(-4)). We did not observe exome-wide significant associations (after correcting for multiple hypothesis testing) in single variant or gene-level testing in the overall case-control or case-case analyses of disease aggressiveness. In this first whole-exome sequencing study of prostate cancer, our findings do not provide strong support for the hypothesis that NS coding variants down to 0.5-1.0% frequency have large effects on prostate cancer risk in men of African ancestry. Higher-coverage sequencing efforts in larger samples will be needed to study rarer variants with smaller effect sizes associated with prostate cancer risk.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Análise de Sequência de DNA , Adulto , Idoso , Exoma , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/epidemiologia , Risco
14.
Cancer Epidemiol Biomarkers Prev ; 25(1): 193-200, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26637267

RESUMO

BACKGROUND: DNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility. METHODS: We conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling. RESULTS: We identified three susceptibility DNA repair genes, RAD51B (P < 5.09 × 10(-6)), MSH5 (P < 5.09 × 10(-6)), and BRCA2 (P = 5.70 × 10(-6)). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways. CONCLUSIONS: Only three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways. IMPACT: Results suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Transdução de Sinais/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/patologia , Dano ao DNA/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/patologia , Masculino , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/patologia , Fatores de Risco
15.
Genet Epidemiol ; 40(1): 57-65, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26639010

RESUMO

Several methods have been proposed to increase power in rare variant association testing by aggregating information from individual rare variants (MAF < 0.005). However, how to best combine rare variants across multiple ethnicities and the relative performance of designs using different ethnic sampling fractions remains unknown. In this study, we compare the performance of several statistical approaches for assessing rare variant associations across multiple ethnicities. We also explore how different ethnic sampling fractions perform, including single-ethnicity studies and studies that sample up to four ethnicities. We conducted simulations based on targeted sequencing data from 4,611 women in four ethnicities (African, European, Japanese American, and Latina). As with single-ethnicity studies, burden tests had greater power when all causal rare variants were deleterious, and variance component-based tests had greater power when some causal rare variants were deleterious and some were protective. Multiethnic studies had greater power than single-ethnicity studies at many loci, with inclusion of African Americans providing the largest impact. On average, studies including African Americans had as much as 20% greater power than equivalently sized studies without African Americans. This suggests that association studies between rare variants and complex disease should consider including subjects from multiple ethnicities, with preference given to genetically diverse groups.


Assuntos
Grupos Étnicos/genética , Variação Genética , Afro-Americanos/genética , Grupo com Ancestrais do Continente Africano/genética , Americanos Asiáticos/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Hispano-Americanos/genética , Humanos , Modelos Genéticos , Análise de Sequência de DNA
16.
Am J Clin Nutr ; 102(5): 1142-57, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26447150

RESUMO

BACKGROUND: Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. OBJECTIVE: The objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, α-tocopherol, and γ-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors. DESIGN: Principal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets. RESULTS: Data were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For α-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). γ-Tocopherol was not associated with risk. CONCLUSIONS: Overall prostate cancer risk was positively associated with retinol and inversely associated with α-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and α-tocopherol. Whether these associations reflect causal relations is unclear.


Assuntos
Carotenoides/sangue , Neoplasias da Próstata/sangue , Vitamina A/sangue , alfa-Tocoferol/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Humanos , Licopeno , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Estudos Observacionais como Assunto , Estudos Prospectivos , Próstata/patologia , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Fatores de Risco
17.
Am J Epidemiol ; 182(11): 917-25, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26493265

RESUMO

We prospectively examined the association between smoking and the risk of breast cancer in a racially/ethnically diverse population comprising mainly women who did not drink alcohol. From 1993 to 2010, we followed 83,300 women who were enrolled in the Multiethnic Cohort Study at 45-75 years of age. We identified cancer cases via linkage to the Surveillance, Epidemiology, and End Results Program cancer registries that covered the states of Hawaii and California through December 2010. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals while adjusting for confounders that were decided a priori. During a mean follow-up of 15 years, 4,484 women developed invasive breast cancer. Compared with parous never smokers, women who had smoked for more than 20 pack-years and initiated smoking more than 5 years before their first childbirth had an overall risk of breast cancer that was 35% higher (hazard ratio = 1.35, 95% confidence interval: 1.13, 1.63). Among women who did not drink alcohol, the risk was 40% higher (hazard ratio = 1.40, 95% confidence interval: 1.08, 1.81). This higher risk did not significantly differ among racial/ethnic groups (P(interaction) = 0.82). We found that various measures of smoking exposure were associated with a higher risk of breast cancer, especially smoking initiated many years before first childbirth, and that risk did not differ by alcohol consumption (yes vs. no) or racial/ethnic group.


Assuntos
Neoplasias da Mama/etiologia , Fumar/efeitos adversos , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Neoplasias da Mama/epidemiologia , California/epidemiologia , Grupos de Populações Continentais/estatística & dados numéricos , Grupos Étnicos/estatística & dados numéricos , Feminino , Hawaii/epidemiologia , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Programa de SEER , Fumar/epidemiologia
18.
Hum Mol Genet ; 24(25): 7406-20, 2015 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-26483192

RESUMO

Results from genome-wide association studies (GWAS) have indicated that strong single-gene effects are the exception, not the rule, for most diseases. We assessed the joint effects of germline genetic variations through a pathway-based approach that considers the tissue-specific contexts of GWAS findings. From GWAS meta-analyses of lung cancer (12 160 cases/16 838 controls), breast cancer (15 748 cases/18 084 controls) and prostate cancer (14 160 cases/12 724 controls) in individuals of European ancestry, we determined the tissue-specific interaction networks of proteins expressed from genes that are likely to be affected by disease-associated variants. Reactome pathways exhibiting enrichment of proteins from each network were compared across the cancers. Our results show that pathways associated with all three cancers tend to be broad cellular processes required for growth and survival. Significant examples include the nerve growth factor (P = 7.86 × 10(-33)), epidermal growth factor (P = 1.18 × 10(-31)) and fibroblast growth factor (P = 2.47 × 10(-31)) signaling pathways. However, within these shared pathways, the genes that influence risk largely differ by cancer. Pathways found to be unique for a single cancer focus on more specific cellular functions, such as interleukin signaling in lung cancer (P = 1.69 × 10(-15)), apoptosis initiation by Bad in breast cancer (P = 3.14 × 10(-9)) and cellular responses to hypoxia in prostate cancer (P = 2.14 × 10(-9)). We present the largest comparative cross-cancer pathway analysis of GWAS to date. Our approach can also be applied to the study of inherited mechanisms underlying risk across multiple diseases in general.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Variação Genética/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética
19.
Cancer Causes Control ; 26(12): 1709-18, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26358830

RESUMO

PURPOSE: Excess body weight is a risk factor for colorectal cancer (CRC) and may also adversely affect survival in CRC patients. METHODS: This study examined the relation of body mass index (BMI), which was self-reported at cohort entry and after 5.7 ± 0.8 years, with CRC-specific and all-cause survival among 4,204 incident cases of invasive CRC in the multiethnic cohort. Cox regression analysis with age as time metric and BMI as time-varying exposure was applied to estimate hazard ratios (HR) and 95% confidence intervals (CIs) while adjusting for relevant covariates. RESULTS: Over 6.0 ± 4.7 years of follow-up, 1,976 all-cause and 1,095 CRC-specific deaths were recorded. The mean time interval between cohort entry and diagnosis was 7.6 ± 4.7 years. No association with CRC-specific survival was detected in men (HR5units = 0.94; 95%CI 0.84-1.04) or women (HR5units = 0.98; 95%CI 0.89-1.08). In men, all-cause survival also showed no relation with BMI (HR5unit = 0.97; 95%CI 0.90-1.06), whereas it was reduced in women (HR5units = 1.10; 95%CI 1.03-1.18). Interactions of BMI with ethnicity were only significant for obesity. Obese Latino and overweight Native Hawaiian men as well as overweight African-American women experienced significantly better CRC-specific survival than whites. Overweight Japanese men and African-American women had better all-cause survival and obese Latino women had the lowest all-cause survival (HRobese = 1.74; 95%CI 1.08-2.80). CONCLUSIONS: This analysis detected little evidence for an adverse effect of excess body weight on CRC-specific survival, but all-cause survival was reduced in women. These findings suggest that adiposity may be less important for CRC survival than as an etiologic factor.


Assuntos
Peso Corporal , Neoplasias Colorretais/etiologia , Obesidade/complicações , Sobrepeso/complicações , Idoso , Índice de Massa Corporal , Estudos de Coortes , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Regressão , Fatores de Risco , Autorrelato
20.
Oncotarget ; 6(35): 37979-94, 2015 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-26317411

RESUMO

In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , NF-kappa B/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Transdução de Sinais , Neoplasias da Mama/patologia , Feminino , Humanos , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA