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1.
J Natl Cancer Inst ; 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127946

RESUMO

BACKGROUND: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. METHODS: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random effects meta-analysis produced summary estimates. All statistical tests were two-sided. RESULTS: Over a period of 38,369,156 person-years of follow-up, 1,391 gallbladder, 758 intrahepatic bile duct, 1,208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (e.g., current versus never smokers hazard ratio [HR] = 1.69, 95% confidence interval [CI] = 1.34 to 2.13 and 2.22, 95%CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all P-trend<0.01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (e.g., >40 cigarettes/day versus never smokers HR = 2.15, 95%CI: 1.15 to 4.00; P-trend=0.001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming ≥5 versus 0 drinks/day (HR = 2.35, 95%CI = 1.46 to 3.78; P-trend=0.04). There was evidence of statistical heterogeneity between several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. CONCLUSIONS: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

2.
Cancer Res ; 79(15): 3973-3982, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31113819

RESUMO

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

3.
Occup Environ Med ; 76(7): 467-470, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30962255

RESUMO

OBJECTIVES: Permethrin use has been associated with an increased risk of multiple myeloma (MM) among pesticide applicators. However, the biological plausibility and mechanisms underlying this association are not fully understood. The aim of this study was to assess whether exposure to permethrin is related to haematological alterations among occupationally exposed pesticide applicators. METHODS: We conducted a longitudinal study among 33 pesticide applicators in the Biomarkers of Exposure and Effect in Agriculture study comparing haematological parameters in the offseason with the day after permethrin exposure and, for 27 participants, approximately 3 weeks postexposure. Complete blood counts with white blood cell differential and lymphocyte subsets were measured at each visit. Multivariate linear mixed effects models were used to assess the relationship between natural log-transformed haematological parameters and exposure to permethrin. RESULTS: The adjusted geometric mean immature granulocyte count was elevated among pesticide applicators following permethrin exposure compared with their offseason levels (37% increase, 95% CI 6% to 76%). Modest but statistically significant (p<0.05) alterations in red blood cell (RBC) parameters (eg, decreased RBC count and haemoglobin and increased mean corpuscular volume and RBC distribution width-SD) were also observed the day after permethrin use compared with offseason levels; decreases in RBC count and haemoglobin and increases in RBC distribution width-SD persisted approximately 3 weeks after permethrin use. CONCLUSIONS: Altered haematological parameters could be indicative of disrupted haematopoiesis, providing insights into the biological plausibility of the observed association between permethrin use and MM risk among pesticide applicators.

4.
Cancer Causes Control ; 30(4): 311-322, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30805813

RESUMO

PURPOSE: To evaluate cancer incidence in the Agricultural Health Study (AHS), a cohort of private pesticide applicators, their spouses, and commercial applicators, based on 12,420 cancers, adding 5,989 cancers, and 9 years of follow-up since last evaluation. METHODS: We calculated age, year, sex, and race-adjusted standardized incidence ratios (SIR) and 95% confidence intervals (CI) for cancer sites in the AHS relative to the general population. RESULTS: Overall AHS cancer incidence was lower than the general population (SIRprivate = 0.91, CI 0.89-0.93; SIRspouse = 0.89, CI 0.86-0.92; SIRcommercial = 0.83, CI 0.76-0.92), with notable deficits across applicators and spouses for oral cavity, pancreas, and lung cancers. Cancer excesses included prostate cancer, lip cancer, certain B-cell lymphomas (e.g., multiple myeloma), acute myeloid leukemia (AML), thyroid cancer, testicular cancer, and peritoneal cancer. The lung cancer deficit was strongest among applicators reporting potential exposure to endotoxin at study enrollment (tasks such as raising animals and handling stored grain). CONCLUSIONS: Although an overall deficit in cancer was observed, there were notable exceptions, including newly observed excesses for AML, thyroid, testicular, and peritoneal cancers. Furthermore, endotoxin exposure may, in part, account for observed lung cancer incidence deficits. Cancer incidence patterns in the AHS suggest farm exposures' relevance to cancer etiology.


Assuntos
Neoplasias/epidemiologia , Exposição Ocupacional/efeitos adversos , Praguicidas , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Cônjuges/estatística & dados numéricos
6.
Int J Cancer ; 144(1): 43-48, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29971781

RESUMO

The epidemiologic evidence regarding the relationship between alcohol consumption and multiple myeloma (MM) risk remains limited and inconsistent, although recent studies suggest a potential protective effect. We prospectively investigated the risk of MM in relation to alcohol consumption frequency among 499,292 participants enrolled in the National Institutes of Health (NIH)-AARP Diet and Health Study in 1995-1996. A total of 1,312 MM cases were identified during follow-up through December 2011. Hazard ratios (HR) and 95% confidence intervals (CI) for categories of alcohol consumption relative to those defined as light drinkers (<1 drink/week) were estimated using multivariate Cox proportional hazard models. Overall, increasing frequency of alcohol consumption was inversely associated with MM (p-trend = 0.01), with a statistically significant association among those who consumed 2 drinks per day (HR = 0.70, 95% CI: 0.50, 0.98); similar but not statistically significant associations were observed for greater frequency of alcohol consumption. Among women, risk of MM was reduced among those who consumed less than one drink per day (HR = 0.73, 95% CI: 0.56, 0.97) and associations with greater frequency of alcohol consumption were inverse although not statistically significant. The findings of this large prospective investigation suggest that moderate alcohol consumption may be associated with reduced future risk of MM.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Dieta , Nível de Saúde , Mieloma Múltiplo/epidemiologia , Idoso , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Inquéritos e Questionários , Estados Unidos/epidemiologia
7.
J Natl Cancer Inst ; 2018 Dec 12.
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.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30375516

RESUMO

Residents of agricultural areas experience pesticide exposures from sources other than direct agricultural work. We developed a quantitative, active ingredient-specific algorithm for cumulative (adult, married lifetime) non-occupational pesticide exposure intensity for spouses of farmers who applied pesticides in the Agricultural Health Study (AHS). The algorithm addressed three exposure pathways: take-home, agricultural drift, and residential pesticide use. Pathway-specific equations combined (i) weights derived from previous meta-analyses of published pesticide exposure data and (ii) information from the questionnaire on frequency and duration of pesticide use by applicators, home proximity to treated fields, residential pesticide usage (e.g., termite treatments), and spouse's off-farm employment (proxy for time at home). The residential use equation also incorporated a published probability matrix that documented the likelihood active ingredients were used in home pest treatment products. We illustrate use of these equations by calculating exposure intensities for the insecticide chlorpyrifos and herbicide atrazine for 19,959 spouses. Non-zero estimates for ≥1 pathway were found for 78% and 77% of spouses for chlorpyrifos and atrazine, respectively. Variability in exposed spouses' intensity estimates was observed for both pesticides, with 75th to 25th percentile ratios ranging from 7.1 to 7.3 for take-home, 6.5 to 8.5 for drift, 2.4 to 2.8 for residential use, and 3.8 to 7.0 for the summed pathways. Take-home and drift estimates were highly correlated (≥0.98), but were not correlated with residential use (0.01‒0.02). This algorithm represents an important advancement in quantifying non-occupational pesticide relative exposure differences and will facilitate improved etiologic analyses in the AHS spouses. The algorithm could be adapted to studies with similar information.

10.
Br J Cancer ; 118(7): 1005-1012, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29520041

RESUMO

BACKGROUND: While tobacco and alcohol are established risk factors for hepatocellular carcinoma (HCC), the most common type of primary liver cancer, it is unknown whether they also increase the risk of intrahepatic cholangiocarcinoma (ICC). Thus, we examined the association between tobacco and alcohol use by primary liver cancer type. METHODS: The Liver Cancer Pooling Project is a consortium of 14 US-based prospective cohort studies that includes data from 1,518,741 individuals (HCC n = 1423, ICC n = 410). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. RESULTS: Current smokers at baseline had an increased risk of HCC (hazard ratio (HR) = 1.86, 95% confidence interval (CI): 1.57-2.20) and ICC (HR = 1.47, 95% CI: 1.07-2.02). Among individuals who quit smoking >30 years ago, HCC risk was almost equivalent to never smokers (HR = 1.09, 95% CI: 0.74-1.61). Compared to non-drinkers, heavy alcohol consumption was associated with an 87% increased HCC risk (HR≥7 drinks/day = 1.87, 95% CI: 1.41-2.47) and a 68% increased ICC risk (HR≥5 drinks/day = 1.68, 95% CI: 0.99-2.86). However, light-to-moderate alcohol consumption of <3 drinks/day appeared to be inversely associated with HCC risk (HR>0-<0.5 drinks/day = 0.77, 95% CI: 0.67-0.89; HR>0.5-<1 drinks/day = 0.57, 95% CI: 0.44-0.73; HR1-<3 drinks/day = 0.71, 95% CI: 0.58-0.87), but not ICC. CONCLUSIONS: These findings suggest that, in this relatively healthy population, smoking cessation and light-to-moderate drinking may reduce the risk of HCC.

11.
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.

12.
J Natl Cancer Inst ; 110(9): 950-958, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29471327

RESUMO

Background: The herbicide alachlor has been widely used in US agriculture since its introduction in 1969. Experimental animal studies show that alachlor causes tumors in vivo; however, few epidemiologic studies have examined associations with human cancer risk. We evaluated alachlor use and cancer incidence in the Agricultural Health Study, updating an earlier analysis that suggested associations with lymphohematopoietic cancers with an additional 540 142 person-years of follow-up and 5113 cancer cases. Methods: Pesticide applicators in Iowa and North Carolina reported lifetime alachlor use at enrollment (1993-1997) and follow-up (1999-2005). Exposure was characterized by cumulative intensity-weighted days. We estimated relative risks (RRs) and 95% confidence intervals (CIs) using Poisson regression for incident cancers from enrollment through 2012(NC)/2013(IA). Models adjusted for age, tobacco, alcohol, and other pesticides. All statistical tests are two-sided. Results: Among 49 685 applicators, 25 640 (51.6%) used alachlor, with 3534 alachlor-exposed cancers. The relative risks of laryngeal cancer (nexposed = 34) increased in the second (RR = 4.68, 95% CI = 1.95 to 11.23), third (RR = 6.04, 95% CI = 2.44 to 14.99), and fourth quartiles (RR = 7.10, 95% CI = 2.58 to 19.53) of intensity-weighted days of use compared with no use (Ptrend = .001). Risk of myeloid leukemia was elevated, though not statistically significantly so, in the fourth quartile of intensity-weighted days of use (RR = 1.82, 95% CI = 0.85 to 3.87, Ptrend = .17). Conclusions: We observed a strong positive association with use of alachlor and laryngeal cancer and a weaker association with myeloid leukemia. The strength and robustness of the association with laryngeal cancer suggests that long-term occupational exposure to alachlor may be a risk factor for laryngeal cancer. This first report requires confirmation.

13.
Cancer Epidemiol Biomarkers Prev ; 27(3): 348-351, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29339358

RESUMO

Background: Although some familial cancer syndromes include biliary tract cancers (BTCs; cancers of the gallbladder, intrahepatic and extrahepatic bile ducts, and ampulla of Vater), the few studies that have examined the relationships between family history of cancer (FHC) and BTCs have reported inconclusive findings. The objective of this study was to investigate the associations of FHC with risk of BTC in the Biliary Tract Cancers Pooling Project (BiTCaPP).Methods: We used Cox proportional hazards regressions models to estimate HRs and 95% confidence intervals for associations between FHC (any, first-degree, in female relative, in male relative, relative with gastrointestinal cancer, and relative with hormonally related cancer) and BTC risk by anatomic site within the biliary tract, adjusting for sex and race/ethnicity. Sensitivity analyses were conducted that restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy.Results: Data on FHC were available from 12 prospective studies within BiTCaPP, which collectively contributed 2,246 cases (729 gallbladder, 345 intrahepatic and 615 extrahepatic bile duct, and 385 ampulla of Vater cancers) with 21,706,107 person-years of follow-up. A marginal, inverse association between FHC and gallbladder cancer was driven to the null when analysis was restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. FHC was not associated with risk of BTC at the other anatomic sites.Conclusions: These findings do not support an association between FHC and BTCs.Impact: In a study of 1.5 million people, FHC is not a risk factor for BTCs. Cancer Epidemiol Biomarkers Prev; 27(3); 348-51. ©2018 AACR.

14.
J Natl Cancer Inst ; 110(5): 509-516, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29136183

RESUMO

Background: Glyphosate is the most commonly used herbicide worldwide, with both residential and agricultural uses. In 2015, the International Agency for Research on Cancer classified glyphosate as "probably carcinogenic to humans," noting strong mechanistic evidence and positive associations for non-Hodgkin lymphoma (NHL) in some epidemiologic studies. A previous evaluation in the Agricultural Health Study (AHS) with follow-up through 2001 found no statistically significant associations with glyphosate use and cancer at any site. Methods: The AHS is a prospective cohort of licensed pesticide applicators from North Carolina and Iowa. Here, we updated the previous evaluation of glyphosate with cancer incidence from registry linkages through 2012 (North Carolina)/2013 (Iowa). Lifetime days and intensity-weighted lifetime days of glyphosate use were based on self-reported information from enrollment (1993-1997) and follow-up questionnaires (1999-2005). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounders, including use of other pesticides. All statistical tests were two-sided. Results: Among 54 251 applicators, 44 932 (82.8%) used glyphosate, including 5779 incident cancer cases (79.3% of all cases). In unlagged analyses, glyphosate was not statistically significantly associated with cancer at any site. However, among applicators in the highest exposure quartile, there was an increased risk of acute myeloid leukemia (AML) compared with never users (RR = 2.44, 95% CI = 0.94 to 6.32, Ptrend = .11), though this association was not statistically significant. Results for AML were similar with a five-year (RRQuartile 4 = 2.32, 95% CI = 0.98 to 5.51, Ptrend = .07) and 20-year exposure lag (RRTertile 3 = 2.04, 95% CI = 1.05 to 3.97, Ptrend = .04). Conclusions: In this large, prospective cohort study, no association was apparent between glyphosate and any solid tumors or lymphoid malignancies overall, including NHL and its subtypes. There was some evidence of increased risk of AML among the highest exposed group that requires confirmation.

15.
Eur J Cancer ; 87: 92-100, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29132062

RESUMO

BACKGROUND: Early-onset prostate cancer is often more aggressive and may have a different aetiology than later-onset prostate cancer, but has been relatively little studied to date. We evaluated occupation in relation to early- and later-onset prostate cancer in a large pooled study. METHODS: We used occupational information from census data in five Nordic countries from 1960 to 1990. We identified prostate cancer cases diagnosed from 1961 to 2005 by linkage of census information to national cancer registries and calculated standardised incidence ratios (SIRs) separately for men aged 30-49 and those aged 50 or older. We also conducted separate analyses by period of follow-up, 1961-1985 and 1986-2005, corresponding to pre- and post-prostate-specific antigen (PSA) screening. RESULTS: For early-onset prostate cancer (n = 1521), we observed the highest SIRs for public safety workers (e.g. firefighters) (SIR = 1.71, 95% confidence interval [CI]: 1.23-2.31) and military personnel (SIR = 1.97, 95% CI: 1.31-2.85). These SIRs were significantly higher than the SIRs for later-onset disease (for public safety workers, SIR = 1.10, 95% CI: 1.07-1.14 and for military personnel, SIR = 1.09, 95% CI: 1.05-1.13; pheterogeneity = 0.005 and 0.002, respectively). Administrators and technical workers also demonstrated significantly increased risks for early-onset prostate cancer, but the SIRs did not differ from those of later-onset disease (pheterogeneity >0.05). While our early-onset finding for public safety workers was restricted to the post-PSA period, that for military personnel was restricted to the pre-PSA period. CONCLUSION: Our results suggest that occupational exposures, particularly for military personnel, may be associated with early-onset prostate cancer. Further evaluation is needed to explain these findings.


Assuntos
Doenças Profissionais/epidemiologia , Saúde do Trabalhador , Ocupações , Neoplasias da Próstata/epidemiologia , Adulto , Idade de Início , Humanos , Incidência , Descrição de Cargo , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Militares , Doenças Profissionais/sangue , Doenças Profissionais/diagnóstico , Exposição Ocupacional/efeitos adversos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Setor Público , Medição de Risco , Fatores de Risco , Países Escandinavos e Nórdicos/epidemiologia
16.
Hum Mol Genet ; 26(24): 4886-4895, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29036293

RESUMO

Known high-risk cutaneous malignant melanoma (CMM) genes account for melanoma risk in <40% of melanoma-prone families, suggesting the existence of additional high-risk genes or perhaps a polygenic mechanism involving multiple genetic modifiers. The goal of this study was to systematically characterize rare germline variants in 42 established melanoma genes among 144 CMM patients in 76 American CMM families without known mutations using data from whole-exome sequencing. We identified 68 rare (<0.1% in public and in-house control datasets) nonsynonymous variants in 25 genes. We technically validated all loss-of-function, inframe insertion/deletion, and missense variants predicted as deleterious, and followed them up in 1, 559 population-based CMM cases and 1, 633 controls. Several of these variants showed disease co-segregation within families. Of particular interest, a stopgain variant in TYR was present in five of six CMM cases/obligate gene carriers in one family and a single population-based CMM case. A start gain variant in the 5'UTR region of PLA2G6 and a missense variant in ATM were each seen in all three affected people in a single family, respectively. Results from rare variant burden tests showed that familial and population-based CMM patients tended to have higher frequencies of rare germline variants in albinism genes such as TYR, TYRP1, and OCA2 (P < 0.05). Our results suggest that rare nonsynonymous variants in low- or intermediate-risk CMM genes may influence familial CMM predisposition, warranting further investigation of both common and rare variants in genes affecting functionally important pathways (such as melanogenesis) in melanoma risk assessment.


Assuntos
Mutação em Linhagem Germinativa , Melanoma/genética , Neoplasias Cutâneas/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Fosfolipases A2 do Grupo VI/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Risco , Sequenciamento Completo do Exoma/métodos
17.
Environ Health ; 16(1): 95, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28874165

RESUMO

BACKGROUND: Organochlorine insecticides (OCs) have historically been used worldwide to control insects, although most have now been banned in developed countries. Evidence for an association between OC exposures and cancer predominantly comes from occupational and population based-studies among men. We evaluated the association between the use of specific OCs and cancer among the female spouses of pesticide applicators in the Agricultural Health Study. METHODS: At enrollment (1993-1997), spouses of private applicators in the cohort provided information about their own use of pesticides, including seven OCs (aldrin, chlordane, dieldrin, DDT, heptachlor, lindane, and toxaphene), and information on potential confounders. We used Poisson regression to estimate relative risks (RRs) and 95% confidence intervals (CIs) for cancers (n ≥ 3 exposed cases) reported to state cancer registries from enrollment through 2012 (North Carolina) and 2013 (Iowa), and use of the individual OCs, as well as use of any of the specific OCs. RESULTS: Among 28,909 female spouses, 2191 (7.58%) reported ever use of at least one OC, of whom 287 were diagnosed with cancer. Most cancers were not associated with OC use. Risk of glioma was increased among users of at least one OC (Nexposed = 11, RR = 3.52, 95% CI 1.72-7.21) and specifically among lindane users (Nexposed = 3, RR = 4.45, 95% CI 1.36-14.55). Multiple myeloma was associated with chlordane (Nexposed = 6, RR = 2.71, 95% CI 1.12-6.55). Based on 3 exposed cases each, there were also positive associations between pancreatic cancer and lindane, and ER-PR- breast cancer and dieldrin. No other associations with breast cancer were found. CONCLUSIONS: Overall, there were some associations with OC use and cancer incidence, however we were limited by the small number of exposed cancer cases. Future research should attempt to expand on these findings by assessing environmental sources of OC exposures, to fully evaluate the role of OC exposures on cancer risk in women.


Assuntos
Exposição Ambiental , Hidrocarbonetos Clorados/toxicidade , Inseticidas/toxicidade , Neoplasias/epidemiologia , Cônjuges/estatística & dados numéricos , Adulto , Idoso , Agricultura , Feminino , Humanos , Incidência , Iowa/epidemiologia , Pessoa de Meia-Idade , Neoplasias/induzido quimicamente , North Carolina/epidemiologia , Estudos Prospectivos , Risco , Adulto Jovem
18.
Eur Urol ; 72(5): 747-754, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28797570

RESUMO

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Homeostase do Telômero , Telômero/genética , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Leucócitos/química , Análise da Randomização Mendeliana , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , Telômero/patologia
19.
Cancer Epidemiol Biomarkers Prev ; 26(6): 876-885, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28223430

RESUMO

Background: Multiple myeloma risk increases with higher adult body mass index (BMI). Emerging evidence also supports an association of young adult BMI with multiple myeloma. We undertook a pooled analysis of eight case-control studies to further evaluate anthropometric multiple myeloma risk factors, including young adult BMI.Methods: We conducted multivariable logistic regression analysis of usual adult anthropometric measures of 2,318 multiple myeloma cases and 9,609 controls, and of young adult BMI (age 25 or 30 years) for 1,164 cases and 3,629 controls.Results: In the pooled sample, multiple myeloma risk was positively associated with usual adult BMI; risk increased 9% per 5-kg/m2 increase in BMI [OR, 1.09; 95% confidence interval (CI), 1.04-1.14; P = 0.007]. We observed significant heterogeneity by study design (P = 0.04), noting the BMI-multiple myeloma association only for population-based studies (Ptrend = 0.0003). Young adult BMI was also positively associated with multiple myeloma (per 5-kg/m2; OR, 1.2; 95% CI, 1.1-1.3; P = 0.0002). Furthermore, we observed strong evidence of interaction between younger and usual adult BMI (Pinteraction <0.0001); we noted statistically significant associations with multiple myeloma for persons overweight (25-<30 kg/m2) or obese (30+ kg/m2) in both younger and usual adulthood (vs. individuals consistently <25 kg/m2), but not for those overweight or obese at only one time period.Conclusions: BMI-associated increases in multiple myeloma risk were highest for individuals who were overweight or obese throughout adulthood.Impact: These findings provide the strongest evidence to date that earlier and later adult BMI may increase multiple myeloma risk and suggest that healthy BMI maintenance throughout life may confer an added benefit of multiple myeloma prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 876-85. ©2017 AACR.


Assuntos
Antropometria/métodos , Índice de Massa Corporal , Mieloma Múltiplo/etiologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Fatores de Risco
20.
Cancer Epidemiol Biomarkers Prev ; 26(5): 769-778, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28035020

RESUMO

Background: Cigarettes are well known to cause cancer, but less is known about the risks of other tobacco products and use of more than one product.Methods: We examined cancer incidence in relation to exclusive use of six tobacco products [cigarettes, other combustibles (pipe, cigar, cigarillo), and smokeless tobacco (chewing tobacco, snuff)] in the Agricultural Health Study. We also examined the added cancer risks associated with use of cigarettes and other tobacco products.Results: In our study population of 84,015, ever use of smokeless tobacco was higher than the general United States population, whereas cigarette use was lower and other combustible product use was about the same. The strongest associations for exclusive ever use were for lung cancer [cigarettes HR = 15.48; 95% confidence interval (CI), 11.95-20.06; other combustible tobacco HR = 3.44; 95% CI, 1.53-7.71; smokeless tobacco HR = 2.21; 95% CI, 1.11-4.42]. Compared with exclusive cigarette smokers, cigarette smokers who additionally ever-used another combustible product had higher risks of smoking-related cancers (HR = 1.16; 95% CI, 1.04-1.30), especially among those who smoked cigarettes for more than 15 years.Conclusions and Impact: Cigarette smokers who additionally ever used smokeless tobacco had cancer risks similar to exclusive cigarette smokers. Users of cigarettes and other combustible tobacco may have higher risks of certain cancers than exclusive cigarette users. Cancer Epidemiol Biomarkers Prev; 26(5); 769-78. ©2016 AACR.


Assuntos
Neoplasias/epidemiologia , Neoplasias/etiologia , Produtos do Tabaco/efeitos adversos , Uso de Tabaco/efeitos adversos , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Uso de Tabaco/epidemiologia , Estados Unidos
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