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1.
Nat Commun ; 12(1): 970, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579919

RESUMO

Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.


Assuntos
Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/genética , Epidemiologia Molecular , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
2.
Cancer Res ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293427

RESUMO

To identify rare variants associated with prostate cancer (PrCa) susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of PrCa genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 PrCa cases, 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 PrCa cases, 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome-wide in a meta-analysis. Gene-based rare variant tests implicated a known PrCa gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. Additionally, a polygenic risk score (PRS) of 188 PrCa variants was strongly associated with risk (90th vs. 40-60th percentile OR = 2.62, P = 2.55*10-191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a six-fold difference in log-probability of Androgen Receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms can help clarify the full genetic architecture of PrCa and other complex traits.

3.
Nat Commun ; 11(1): 6084, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247094

RESUMO

Cancer risk is determined by a complex interplay of environmental and heritable factors. Polygenic risk scores (PRS) provide a personalized genetic susceptibility profile that may be leveraged for disease prediction. Using data from the UK Biobank (413,753 individuals; 22,755 incident cancer cases), we quantify the added predictive value of integrating cancer-specific PRS with family history and modifiable risk factors for 16 cancers. We show that incorporating PRS measurably improves prediction accuracy for most cancers, but the magnitude of this improvement varies substantially. We also demonstrate that stratifying on levels of PRS identifies significantly divergent 5-year risk trajectories after accounting for family history and modifiable risk factors. At the population level, the top 20% of the PRS distribution accounts for 4.0% to 30.3% of incident cancer cases, exceeding the impact of many lifestyle-related factors. In summary, this study illustrates the potential for improving cancer risk assessment by integrating genetic risk scores.

4.
Genome Med ; 12(1): 93, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109261

RESUMO

BACKGROUND: Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities. METHODS: We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort. RESULTS: Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRß1 at positions 11, 13, 71, and 74 for Epstein-Barr virus (EBV), Varicella zoster virus (VZV), human herpesvirus 7, (HHV7), and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P < 5.0 × 10-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, and CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P = 5.0 × 10-15 (MCV), NTN5: P = 1.1 × 10-9 (BKV), and P2RY13: P = 1.1 × 10-8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases, from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions. CONCLUSIONS: Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.

5.
Nat Commun ; 11(1): 4423, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887889

RESUMO

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.


Assuntos
Carcinogênese/genética , Neoplasias/genética , Adulto , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
6.
medRxiv ; 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32511533

RESUMO

Introduction: Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and informs public health interventions. Methods: We conducted a comprehensive study linking germline genetic variation and gene expression with antibody response to 28 antigens for 16 viruses using serological data from 7924 participants in the UK Biobank cohort. Using test results from 2010 UK Biobank subjects, we also investigated genetic determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Results: Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. Genome-wide association analyses discovered 7 novel genetic loci associated with viral antibody response (P<5.0×10-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for Merkel cell polyomavirus (MCV), as well as CXCR5 (11q23.3) and TBKBP1 (17q21.32) for human herpesvirus 7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P=5.0×10-15 (MCV), NTN5: P=1.1×10-9 (BKV), and P2RY13: P=1.1×10-8 (Epstein-Barr virus nuclear antigen). We also demonstrated pleiotropy between viral response genes and complex diseases, such as C4A expression in varicella zoster virus and schizophrenia. Finally, our analyses of SARS-CoV-2 revealed the first genome-wide significant infection susceptibility signal in EHF, an epithelial-specific transcriptional repressor implicated in airway disease. Targeted analyses of expression quantitative trait loci suggest a possible role for tissue-specific ACE2 expression in modifying SARS-CoV-2 susceptibility. Conclusions: Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants of host-virus interaction. Our results may have implications for complex disease etiology and COVID-19.

7.
Int J Cancer ; 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32574374

RESUMO

Insecticide use has been linked to increased risk of non-Hodgkin lymphoma (NHL), however, findings of epidemiologic studies have been inconsistent, particularly for NHL subtypes. We analyzed 1690 NHL cases and 5131 controls in the North American Pooled Project (NAPP) to investigate self-reported insecticide use and risk of NHL overall and by subtypes: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and small lymphocytic lymphoma (SLL). Odds ratios (OR) and 95% confidence intervals for each insecticide were estimated using logistic regression. Subtype-specific associations were evaluated using ASSET (Association analysis for SubSETs). Increased risks of multiple NHL subtypes were observed for lindane (OR = 1.60, 1.20-2.10: FL, DLCBL, SLL), chlordane (OR = 1.59, 1.17-2.16: FL, SLL) and DDT (OR = 1.36, 1.06-1.73: DLBCL, SLL). Positive trends were observed, within the subsets with identified associations, for increasing categories of exposure duration for lindane (Ptrend = 1.7 × 10-4 ), chlordane (Ptrend = 1.0 × 10-3 ) and DDT (Ptrend = 4.2 × 10-3 ), however, the exposure-response relationship was nonlinear. Ever use of pyrethrum was associated with an increased risk of FL (OR = 3.65, 1.45-9.15), and the relationship with duration of use appeared monotonic (OR for >10 years: OR = 5.38, 1.75-16.53; Ptrend = 3.6 × 10-3 ). Our analysis identified several novel associations between insecticide use and specific NHL subtypes, suggesting possible etiologic heterogeneity in the context of pesticide exposure.

8.
Cancer Causes Control ; 31(6): 583-599, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32314107

RESUMO

PURPOSE: The purpose of this study was to investigate associations between pesticide exposures and risk of Hodgkin lymphoma (HL) using data from the North American Pooled Project (NAPP). METHODS: Three population-based studies conducted in Kansas, Nebraska, and six Canadian provinces (HL = 507, Controls = 3886) were pooled to estimate odds ratios and 95% confidence intervals for single (never/ever) and multiple (0, 1, 2-4, ≥ 5) pesticides used, duration (years) and, for select pesticides, frequency (days/year) using adjusted logistic regression models. An age-stratified analysis (≤ 40/ > 40 years) was conducted when numbers were sufficient. RESULTS: In an analysis of 26 individual pesticides, ever use of terbufos was significantly associated with HL (OR: 2.53, 95% CI 1.04-6.17). In age-stratified analyses, associations were stronger among those ≤ 40 years of age. No significant associations were noted among those > 40 years old; however, HL cases ≤ 40 were three times more likely to report ever using dimethoate (OR: 3.76 95% CI 1.02-33.84) and almost twice as likely to have ever used malathion (OR: 1.86 95% CI 1.00-3.47). Those ≤ 40 years of age reporting use of 5 + organophosphate insecticides had triple the odds of HL (OR: 3.00 95% CI 1.28-7.03). Longer duration of use of 2,4-D, ≥ 6 vs. 0 years, was associated with elevated odds of HL (OR: 2.59 95% CI 1.34-4.97). CONCLUSION: In the NAPP, insecticide use may increase the risk of HL, but results are based on small numbers.


Assuntos
Exposição Ambiental/estatística & dados numéricos , Doença de Hodgkin/epidemiologia , Praguicidas , Adulto , Canadá/epidemiologia , Humanos , Kansas/epidemiologia , Nebraska/epidemiologia
9.
BMC Cancer ; 20(1): 171, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32126982

RESUMO

BACKGROUND: Silica and asbestos are recognized lung carcinogens. However, their role in carcinogenesis at other organs is less clear. Clearance of inhaled silica particles and asbestos fibers from the lungs may lead to translocation to sites such as the bladder where they may initiate carcinogenesis. We used data from a Canadian population-based case-control study to evaluate the associations between these workplace exposures and bladder cancer. METHODS: Data from a population-based case-control study were used to characterize associations between workplace exposure to silica and asbestos and bladder cancer among men. Bladder cancer cases (N = 658) and age-frequency matched controls (N = 1360) were recruited within the National Enhanced Cancer Surveillance System from eight Canadian provinces (1994-97). Exposure concentration, frequency and reliability for silica and asbestos were assigned to each job, based on lifetime occupational histories, using a combination of job-exposure profiles and expert review. Exposure was modeled as ever/never, highest attained concentration, duration (years), highest attained frequency (% worktime) and cumulative exposure. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated using adjusted logistic regression. RESULTS: A modest (approximately 20%) increase in bladder cancer risk was found for ever having been exposed to silica, highest attained concentration and frequency of exposure but this increase was not statistically significant. Relative to unexposed, the odds of bladder cancer were 1.41 (95%CI: 1.01-1.98) times higher among men exposed to silica at work for ≥27 years. For asbestos, relative to unexposed, an increased risk of bladder cancer was observed for those first exposed ≥20 years ago (OR:2.04, 95%CI:1.25-3.34), those with a frequency of exposure of 5-30% of worktime (OR:1.45, 95%CI:1.06-1.98), and for those with < 10 years of exposure at low concentrations (OR:1.75, 95%CI:1.10-2.77) and the lower tertile of cumulative exposure (OR:1.69, 95%CI:1.07-2.65). However, no clear exposure-response relationships emerged. CONCLUSIONS: Our results indicate a slight increase in risk of bladder cancer with exposure to silica and asbestos, suggesting that the effects of these agents are broader than currently recognized. The findings from this study inform evidence-based action to enhance cancer prevention efforts, particularly for workers in industries with regular exposure.


Assuntos
Asbestos/efeitos adversos , Doenças Profissionais/epidemiologia , Dióxido de Silício/efeitos adversos , Neoplasias da Bexiga Urinária/epidemiologia , Adulto , Idoso , Canadá , Estudos de Casos e Controles , Medicina Baseada em Evidências , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/estatística & dados numéricos , Neoplasias da Bexiga Urinária/induzido quimicamente
10.
Nat Commun ; 11(1): 27, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911640

RESUMO

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.


Assuntos
Neoplasias Pulmonares/genética , Pulmão/fisiopatologia , Adulto , Idoso , Feminino , Volume Expiratório Forçado , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Testes de Função Respiratória , Capacidade Vital
11.
Occup Environ Med ; 76(9): 668-671, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31413189

RESUMO

OBJECTIVES: The causes of kidney cancer are not well understood though occupational exposures are thought to play a role. Crystalline silica is a known human carcinogen, and despite previous links with kidney disease, there have been few studies investigating its association with kidney cancer. We addressed this research gap using a population-based case-control study of Canadian men. METHODS: Questionnaire data were obtained from individuals with histologically confirmed kidney cancer, and population-based controls recruited from eight Canadian provinces (1994-1997). An industrial hygienist characterised participants' lifetime occupational exposure, and their confidence in the assessment (possibly, probably or definitely exposed) to silica on three dimensions (intensity, frequency and duration), and cumulative exposure was estimated. Logistic regression was used to estimate ORs and 95% CIs, adjusting for potential confounders. RESULTS: Nearly half of the 689 kidney cancer cases (49%) and 2369 controls (44%) had ever been occupationally exposed to crystalline silica. In a fully adjusted model, workers ever-exposed to silica had a slightly increased risk of kidney cancer relative to those who were unexposed (OR 1.10, 95% CI 0.92 to 1.32). Odds were modestly (and generally not statistically significantly) increased for models with duration of exposure and cumulative exposure, though exposure-response relationships were not evident. CONCLUSIONS: Our findings do not provide evidence that occupational exposure to crystalline silica increases risk of kidney cancer in men.


Assuntos
Neoplasias Renais/epidemiologia , Exposição Ocupacional , Dióxido de Silício/efeitos adversos , Adulto , Idoso , Canadá/epidemiologia , Estudos de Casos e Controles , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários
12.
Nat Commun ; 10(1): 3948, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462633

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

13.
Nat Commun ; 10(1): 3107, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308362

RESUMO

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.


Assuntos
Próstata/metabolismo , Neoplasias da Próstata/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Perfilação da Expressão Gênica , Humanos , Masculino , Modelos Genéticos , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transcriptoma
14.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1228-1237, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31263055

RESUMO

BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus. METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases. RESULTS: Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3). CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration. IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.


Assuntos
Variação Genética/genética , Leucócitos/metabolismo , Neoplasias Pulmonares/genética , Telômero/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco
15.
Environ Int ; 127: 199-205, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30928843

RESUMO

Organophosphates and carbamates have been among the most commonly used insecticides, with both agricultural and residential uses. Previous studies have suggested associations of non-Hodgkin lymphoma (NHL) with some of these chemicals; however, many studies have been limited in their ability to evaluate associations with lymphoma subtypes. We evaluated the use of eleven organophosphate and two carbamate insecticides in association with NHL in the North American Pooled Project, which includes data from case-control studies in the United States and Canada (1690 cases/5131 controls). We used unconditional logistic regression adjusting for potential confounders, including use of other pesticides, to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between these chemicals and NHL overall, and NHL subtypes, i.e., follicular (FL), diffuse large B-cell (DLBCL), small lymphocytic lymphoma (SLL) and others. Ever use of malathion was associated with increased risk of NHL overall (OR = 1.43; 95% CI: 1.14-1.81) compared with never users. Categories using tertiles of duration (<4 yrs., 4-12 yrs., and >12 yrs) also showed a significant exposure-response for increasing years of use of malathion and risk of NHL (OR<4vsUnex = 1.33 (0.88, 2.03), OR4-12vsUnex = 1.42 (1.02, 1.96), OR>12vsUnex = 1.55 (1.05, 2.28, p-trend < 0.01)). In addition, malathion use was statistically significantly associated with FL (OR = 1.58; 95% CI: 1.11-2.27) and DLBCL (OR = 1.61; 95% CI: 1.16-2.22) while there were no apparent associations with SLL or other subtypes, the p-value for heterogeneity across subtypes, however, was not significant. These results support previous studies suggesting an association between insecticide use and NHL overall, and provide new information on associations with NHL subtypes.


Assuntos
Carbamatos/toxicidade , Inseticidas/toxicidade , Linfoma não Hodgkin/induzido quimicamente , Organofosfatos/toxicidade , Idoso , Canadá , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Praguicidas , Fatores de Risco , Estados Unidos
16.
Cancer Epidemiol Biomarkers Prev ; 28(5): 935-942, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30700444

RESUMO

BACKGROUND: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. METHODS: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. RESULTS: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. CONCLUSIONS: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. IMPACT: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.


Assuntos
Adenocarcinoma de Pulmão/sangue , Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma de Células Escamosas/sangue , Neoplasias Pulmonares/sangue , Carcinoma de Pequenas Células do Pulmão/sangue , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Análise da Randomização Mendeliana , Contagem de Plaquetas , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia
18.
Int J Epidemiol ; 48(3): 751-766, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30059977

RESUMO

BACKGROUND: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. METHODS: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. RESULTS: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. CONCLUSIONS: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.


Assuntos
Adenocarcinoma de Pulmão/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Leucócitos/metabolismo , Neoplasias Pulmonares/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Homeostase do Telômero/genética , Telômero/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade
19.
Can J Public Health ; 109(4): 464-472, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30225576

RESUMO

OBJECTIVE: Previous studies considered the role of occupational causes in kidney cancer but were limited by small sample sizes and imprecise exposure assessment. This study examined the relationship between occupational exposure to asbestos and the risk of kidney cancer across a range of jobs in a large, population-based case-control study in Canada. METHODS: Data were from the case-control component of the National Enhanced Cancer Surveillance System, a study conducted between 1994 and 1997 in eight Canadian provinces. Male kidney cancer cases, histologically confirmed, and controls completed questionnaires on socio-demographics, anthropometry, diet, smoking, secondhand smoke exposure, and physical activity. Occupational histories were also collected, including each job held for at least 1 year since the age of 18. Occupational hygienists, blinded to case status, assigned exposure to asbestos, considering intensity, frequency, and probability of exposure (each 3-point scales). Logistic regression was used to estimate the odds of kidney cancer in exposed participants (defined using three metrics) compared to those without asbestos exposure. RESULTS: There were 712 cases and 2454 controls in these analyses. Ever-exposure to asbestos was associated with 20% increased odds of kidney cancer compared to unexposed workers (OR 1.2, 95% confidence interval 1.0-1.4 when including possibly exposed workers). A small increase in risk was observed with cumulative exposure, while increasing intensity of exposure was related to increased odds of kidney cancer. CONCLUSIONS: This study found some evidence for an association between occupational exposure to asbestos and kidney cancer. Higher intensity of exposure to asbestos had the strongest relationship with kidney cancer risk.


Assuntos
Asbestos/toxicidade , Neoplasias Renais/induzido quimicamente , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Canadá/epidemiologia , Estudos de Casos e Controles , Humanos , Neoplasias Renais/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/epidemiologia , Exposição Ocupacional/estatística & dados numéricos , Fatores de Risco
20.
Ann Work Expo Health ; 62(8): 978-989, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30059990

RESUMO

Introduction: Kidney cancer is the fifth most common incident cancer in Canadian men. Diesel and gasoline exhausts are common workplace exposures that have been examined as risk factors for non-lung cancer sites, including the kidney, but limitations in exposure assessment methods have contributed to inconsistent findings. The objective of this study was to assess the relationship between occupational gasoline and diesel engine exhausts and the risk of kidney cancer in men. Methods: The National Enhanced Cancer Surveillance System (NECSS) is a Canadian population-based case-control study conducted in 1994-1997. Incident kidney cancer cases were identified using provincial registries, while the control series was identified through random-digit dialing, or provincial administrative databases. Self-reported questionnaires were used to obtain information on lifetime occupational history and cancer risk factors. Two hygienists, blinded to case status, coded occupational histories for diesel and gasoline exhaust exposures using concentration, frequency, duration, and reliability. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) separately by exhaust type. The separate and combined impacts of both engine exhausts were also examined. ORs were adjusted for age, province, body mass index, occupational secondhand smoke exposure, and education. Results: Of the kidney cancer cases (n = 712), 372 (52%) had exposure to both exhausts at some point, and 984 (40%) of the controls (n = 2457) were ever exposed. Workers who had ever been exposed to engine exhausts were more likely to have kidney cancer than those who were never exposed (OR diesel = 1.23, 95% CI = 0.99-1.53; OR gasoline = 1.51, 95% CI = 1.23-1.86). Exposure to gasoline exhaust was consistently associated with kidney cancer in a dose-response manner (P value for trends in highest attained and cumulative exposure both <0.0001). Those men with high cumulative exposure to both gasoline and diesel exhaust had a 76% increased odds of kidney cancer (95% CI = 1.27-2.43). Conclusions: This study provides evidence that occupational gasoline, and to a lesser extent, diesel exhaust exposure may increase the risk of kidney cancer.


Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Neoplasias Renais/epidemiologia , Doenças Profissionais/epidemiologia , Exposição Ocupacional/análise , Emissões de Veículos/análise , Adulto , Canadá/epidemiologia , Estudos de Casos e Controles , Gasolina , Humanos , Incidência , Neoplasias Renais/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Razão de Chances , Reprodutibilidade dos Testes , Fatores de Risco , Inquéritos e Questionários
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