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

RESUMO

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

2.
Nat Commun ; 11(1): 27, 2020 Jan 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.

3.
Int J Cancer ; 146(4): 929-942, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31050823

RESUMO

Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow-up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5-25 kg/m2 : HR = 1.94, 95% CI: 1.25-3.03) and women (HR = 2.66, 95% CI: 1.15-6.19); however, adjustment for waist-to-hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99-6.06 for WHR >0.96 vs. <0.91; HR = 2.67, 95% CI: 1.52-4.72 for WC >98 vs. <90 cm) and women (HR = 4.40, 95% CI: 1.35-14.33 for WHR >0.82 vs. <0.76; HR = 5.67, 95% CI: 1.76-18.26 for WC >84 vs. <74 cm). WHR was also positively associated with GC in women, and WC was positively associated with GC in men. Inverse associations were observed between parity and EA (HR = 0.38, 95% CI: 0.14-0.99; >2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32-0.91; >26 vs. <22 years); whereas bilateral ovariectomy was positively associated with GNC (HR = 1.87, 95% CI: 1.04-3.36). These findings support a role for hormonal pathways in upper gastrointestinal cancers.

4.
Int J Cancer ; 146(1): 76-84, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31107546

RESUMO

Four epidemiologic studies have assessed the association between nut intake and pancreatic cancer risk with contradictory results. The present study aims to investigate the relation between nut intake (including seeds) and pancreatic ductal adenocarcinoma (PDAC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to estimate hazards ratio (HR) and 95% confidence intervals (95% CI) for nut intake and PDAC risk. Information on intake of nuts was obtained from the EPIC country-specific dietary questionnaires. After a mean follow-up of 14 years, 476,160 participants were eligible for the present study and included 1,283 PDAC cases. No association was observed between consumption of nuts and PDAC risk (highest intake vs nonconsumers: HR, 0.89; 95% CI, 0.72-1.10; p-trend = 0.70). Furthermore, no evidence for effect-measure modification was observed when different subgroups were analyzed. Overall, in EPIC, the highest intake of nuts was not statistically significantly associated with PDAC risk.

5.
Eur J Epidemiol ; 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31564045

RESUMO

Pancreatic cancer (PC) is a highly fatal cancer with currently limited opportunities for early detection and effective treatment. Modifiable factors may offer pathways for primary prevention. In this study, the association between the Healthy Lifestyle Index (HLI) and PC risk was examined. Within the European Prospective Investigation into Cancer and Nutrition cohort, 1113 incident PC (57% women) were diagnosed from 400,577 participants followed-up for 15 years (median). HLI scores combined smoking, alcohol intake, dietary exposure, physical activity and, in turn, overall and central adiposity using BMI (HLIBMI) and waist-to-hip ratio (WHR, HLIWHR), respectively. High values of HLI indicate adherence to healthy behaviors. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and 95% confidence intervals (CI). Sensitivity analyses were performed by excluding, in turn, each factor from the HLI score. Population attributable fractions (PAF) were estimated assuming participants' shift to healthier lifestyles. The HRs for a one-standard deviation increment of HLIBMI and HLIWHR were 0.84 (95% CI: 0.79, 0.89; ptrend = 4.3e-09) and 0.77 (0.72, 0.82; ptrend = 1.7e-15), respectively. Exclusions of smoking from HLIWHR resulted in HRs of 0.88 (0.82, 0.94; ptrend = 4.9e-04). The overall PAF estimate was 19% (95% CI: 11%, 26%), and 14% (6%, 21%) when smoking was removed from the score. Adherence to a healthy lifestyle was inversely associated with PC risk, beyond the beneficial role of smoking avoidance. Public health measures targeting compliance with healthy lifestyles may have an impact on PC incidence.

6.
Cancer Epidemiol Biomarkers Prev ; 28(6): 1089-1092, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31160392

RESUMO

BACKGROUND: To analyze the potential effect of social inequality on pancreatic cancer risk in Western Europe, by reassessing the association within the European Prospective Investigation into Cancer and Nutrition (EPIC) Study, including a larger number of cases and an extended follow-up. METHODS: Data on highest education attained were gathered for 459,170 participants (70% women) from 10 European countries. A relative index of inequality (RII) based on adult education was calculated for comparability across countries and generations. Cox regression models were applied to estimate relative inequality in pancreatic cancer risk, stratifying by age, gender, and center, and adjusting for known pancreatic cancer risk factors. RESULTS: A total of 1,223 incident pancreatic cancer cases were included after a mean follow-up of 13.9 (±4.0) years. An inverse social trend was found in models adjusted for age, sex, and center for both sexes [HR of RII, 1.27; 95% confidence interval (CI), 1.02-1.59], which was also significant among women (HR, 1.42; 95% CI, 1.05-1.92). Further adjusting by smoking intensity, alcohol consumption, body mass index, prevalent diabetes, and physical activity led to an attenuation of the RII risk and loss of statistical significance. CONCLUSIONS: The present reanalysis does not sustain the existence of an independent social inequality influence on pancreatic cancer risk in Western European women and men, using an index based on adult education, the most relevant social indicator linked to individual lifestyles, in a context of very low pancreatic cancer survival from (quasi) universal public health systems. IMPACT: The results do not support an association between education and risk of pancreatic cancer.

7.
Oncotarget ; 10(19): 1760-1774, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30956756

RESUMO

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

8.
Carcinogenesis ; 40(3): 432-440, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-30590402

RESUMO

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

9.
Int J Cancer ; 144(7): 1511-1521, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30178496

RESUMO

Pancreatic cancer (PC) has an exceptionally low survival rate and primary prevention strategies are limited. Folate plays an important role in one-carbon metabolism and has been associated with the risk of several cancers, but not consistently with PC risk. We aimed to investigate the association between dietary folate intake and PC risk, using the standardised folate database across 10 European countries. A total of 477,206 participants were followed up for 11 years, during which 865 incident primary PC cases were recorded. Folate intake was energy-adjusted using the residual method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In multivariable analyses stratified by age, sex, study centre and adjusted for energy intake, smoking status, BMI, educational level, diabetes status, supplement use and dietary fibre intake, we found no significant association between folate intake and PC risk: the HR of PC risk for those in the highest quartile of folate intake (≥353 µg/day) compared to the lowest (<241 µg/day) was 0.81 (95% CI: 0.51, 1.31; ptrend = 0.38). In current smokers, a positive trend was observed in PC risk across folate quartiles [HR = 4.42 (95% CI: 1.05, 18.62) for ≥353 µg/day vs. <241 µg/day, ptrend = 0.01]. Nonetheless, there was no significant interaction between smoking and dietary folate intake (pinteraction = 0.99). We found no association between dietary folate intake and PC risk in this large European study.


Assuntos
Ácido Fólico/administração & dosagem , Neoplasias Pancreáticas/epidemiologia , Fumar/epidemiologia , Adulto , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Neoplasias Pancreáticas/etiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Autorrelato , Fumar/efeitos adversos
10.
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.

11.
Int J Cancer ; 144(8): 1877-1887, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30259989

RESUMO

Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.


Assuntos
Apolipoproteína A-II/sangue , Antígeno CA-19-9/sangue , Detecção Precoce de Câncer/métodos , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , Isoformas de Proteínas/análise , Isoformas de Proteínas/metabolismo , Curva ROC , Fatores de Tempo
12.
Cancer Epidemiol ; 58: 25-32, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30445228

RESUMO

BACKGROUND: There is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders. METHODS: Twenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type. RESULTS: We observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10-19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12-15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for ≥20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90). CONCLUSIONS: Whether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms.


Assuntos
Adenocarcinoma/epidemiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Carcinoma de Células Escamosas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Adenocarcinoma/etiologia , Idoso , Bebidas Alcoólicas/efeitos adversos , Carcinoma de Células Escamosas/etiologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Inquéritos e Questionários
13.
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.

14.
Am J Hum Biol ; 30(6): e23181, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30251288

RESUMO

OBJECTIVE: To determinate the role of lifestyle factors, recent diet, menstrual factors, and reproductive history in age at natural menopause in adult Spanish women. METHODS: In total, 12 562 pre-menopausal women were available for analysis from the EPIC-Spain sub-cohort. Women were recruited between 1992 and 1996 in five regions of Spain (Asturias, Granada, Murcia, Navarra, and San Sebastian) and, for these analyses, were followed for 3 years. Questionnaires on diet, lifestyle, anthropometric measurements, and reproductive and exogenous hormones history were collected at baseline. Menopause status was updated at a median of 3 years of follow-up. RESULTS: After a median of 3 years of follow-up 1166 women became postmenopausal. An earlier age at menopause was observed in current smokers (HR: 1.29; 95%CI 1.08-1.55) and in non-users of oral contraceptives (HR: 1.32; 95%CI 1.01-1.57). A later age at menopause was observed in women with irregular menses (HR: 0.71; 95%CI 0.56-0.91) and in women with a higher number of pregnancies (HR: 0.74; 95%CI 0.56-0.94). CONCLUSIONS: Our results confirm that women who smoked had an earlier age at natural menopause, while use of oral contraceptives, higher number of pregnancies, and irregularity of menses were associated with a prolonged reproductive lifespan. No associations were observed for dietary habits assessed after the age of 40 years.


Assuntos
Dieta/estatística & dados numéricos , Estilo de Vida , Menopausa/fisiologia , História Reprodutiva , Sucesso Acadêmico , Adulto , Fatores Etários , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Índice de Massa Corporal , Estudos de Coortes , Exercício , Feminino , Humanos , Pessoa de Meia-Idade , Espanha/epidemiologia , Uso de Tabaco/epidemiologia
15.
Carcinogenesis ; 39(8): 1056-1067, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-29800239

RESUMO

Diets with high inflammatory potential are suspected to increase risk for pancreatic cancer (PC). Using pooled analyses, we examined whether this association applies to populations from different geographic regions and population subgroups with varying risks for PC, including variation in ABO blood type. Data from six case-control studies (cases, n = 2414; controls, n = 4528) in the Pancreatic Cancer Case-Control Consortium (PanC4) were analyzed, followed by replication in five nested case-control studies (cases, n = 1268; controls, n = 4215) from the Pancreatic Cancer Cohort Consortium (PanScan). Two polymorphisms in the ABO locus (rs505922 and rs8176746) were used to infer participants' blood types. Dietary questionnaire-derived nutrient/food intake was used to compute energy-adjusted dietary inflammatory index (E-DII®) scores to assess inflammatory potential of diet. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted logistic regression. Higher E-DII scores, reflecting greater inflammatory potential of diet, were associated with increased PC risk in PanC4 [ORQ5 versus Q1=2.20, 95% confidence interval (CI) = 1.85-2.61, Ptrend < 0.0001; ORcontinuous = 1.20, 95% CI = 1.17-1.24], and PanScan (ORQ5 versus Q1 = 1.23, 95% CI = 0.92-1.66, Ptrend = 0.008; ORcontinuous = 1.09, 95% CI = 1.02-1.15). As expected, genotype-derived non-O blood type was associated with increased PC risk in both the PanC4 and PanScan studies. Stratified analyses of associations between E-DII quintiles and PC by genotype-derived ABO blood type did not show interaction by blood type (Pinteraction = 0.10 in PanC4 and Pinteraction=0.13 in PanScan). The results show that consuming a pro-inflammatory diet and carrying non-O blood type are each individually, but not interactively, associated with increased PC risk.


Assuntos
Sistema do Grupo Sanguíneo ABO/genética , Comportamento Alimentar/fisiologia , Inflamação/imunologia , Neoplasias Pancreáticas/sangue , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/complicações , Masculino , Pessoa de Meia-Idade , Pâncreas/imunologia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/imunologia , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Fatores de Risco , Inquéritos e Questionários/estatística & dados numéricos
16.
Cancer Epidemiol Biomarkers Prev ; 27(7): 790-804, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29661801

RESUMO

Background: Neoplastic and non-neoplastic events may raise levels of mucins, CA15.3, and CA125, and generate antibodies against them, but their impact on epithelial ovarian cancer (EOC) risk has not been fully defined.Methods: CA15.3, CA125, and IgG1 antibodies against them were measured in 806 women who developed EOC and 1,927 matched controls from the European Prospective Investigation of Nutrition and Cancer. Associations between epidemiologic factors and anti-mucin antibodies were evaluated using generalized linear models; EOC risks associated with anti-mucin antibodies, by themselves or in combination with respective antigens, were evaluated using conditional logistic regression.Results: In controls, lower antibodies against both mucins were associated with current smoking; and, in postmenopausal women, higher levels with longer oral contraceptive use and later-age-at and shorter-interval-since last birth. Lower anti-CA15.3 antibodies were associated with higher body mass and, in premenopausal women, more ovulatory cycles. Higher anti-CA15.3 and anti-CA125 antibodies were associated with higher risk for mucinous EOC occurring ≥ 3 years from enrollment. Long-term risk for serous EOC was reduced in women with low CA125 and high anti-CA125 antibodies relative to women with low concentrations of both.Conclusions: We found general support for the hypothesis that anti-mucin antibody levels correlate with risk factors for EOC. Antibodies alone or in combinations with their antigen may predict longer term risk of specific EOC types.Impact: Anti-CA125 and anti-CA15.3 antibodies alone or in perspective of antigens may be informative in the pathogenesis of EOC subtypes, but less useful for informing risk for all EOC. Cancer Epidemiol Biomarkers Prev; 27(7); 790-804. ©2018 AACR.


Assuntos
Biomarcadores Tumorais/genética , Antígeno Ca-125/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Fatores de Risco
17.
BMJ Open ; 8(3): e018324, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29593016

RESUMO

PURPOSE: The prevalence of chronic non-communicable diseases (NCDs) is increasing worldwide. NCDs are the leading cause of both morbidity and mortality, and it is estimated that by 2030, they will be responsible for 80% of deaths across the world. The Genomes for Life (GCAT) project is a long-term prospective cohort study that was designed to integrate and assess the role of epidemiological, genomic and epigenomic factors in the development of major chronic diseases in Catalonia, a north-east region of Spain. PARTICIPANTS: At the end of 2017, the GCAT Study will have recruited 20 000 participants aged 40-65 years. Participants who agreed to take part in the study completed a self-administered computer-driven questionnaire, and underwent blood pressure, cardiac frequency and anthropometry measurements. For each participant, blood plasma, blood serum and white blood cells are collected at baseline. The GCAT Study has access to the electronic health records of the Catalan Public Healthcare System. Participants will be followed biannually at least 20 years after recruitment. FINDINGS TO DATE: Among all GCAT participants, 59.2% are women and 83.3% of the cohort identified themselves as Caucasian/white. More than half of the participants have higher education levels, 72.2% are current workers and 42.1% are classified as overweight (body mass index ≥25 and <30 kg/m2). We have genotyped 5459 participants, of which 5000 have metabolome data. Further, the whole genome of 808 participants will be sequenced by the end of 2017. FUTURE PLANS: The first follow-up study started in December 2017 and will end by March 2018. Residences of all subjects will be geocoded during the following year. Several genomic analyses are ongoing, and metabolomic and genomic integrations will be performed to identify underlying genetic variants, as well as environmental factors that influence metabolites.


Assuntos
Genômica/métodos , Doenças não Transmissíveis/epidemiologia , Adulto , Idoso , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Espanha
18.
Int J Cancer ; 143(4): 801-812, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29524225

RESUMO

Recent evidence suggested a weak relationship between alcohol consumption and pancreatic cancer (PC) risk. In our study, the association between lifetime and baseline alcohol intakes and the risk of PC was evaluated, including the type of alcoholic beverages and potential interaction with smoking. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1,283 incident PC (57% women) were diagnosed from 476,106 cancer-free participants, followed up for 14 years. Amounts of lifetime and baseline alcohol were estimated through lifestyle and dietary questionnaires, respectively. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and their 95% confidence interval (CI). Alcohol intake was positively associated with PC risk in men. Associations were mainly driven by extreme alcohol levels, with HRs comparing heavy drinkers (>60 g/day) to the reference category (0.1-4.9 g/day) equal to 1.77 (95% CI: 1.06, 2.95) and 1.63 (95% CI: 1.16, 2.29) for lifetime and baseline alcohol, respectively. Baseline alcohol intakes from beer (>40 g/day) and spirits/liquors (>10 g/day) showed HRs equal to 1.58 (95% CI: 1.07, 2.34) and 1.41 (95% CI: 1.03, 1.94), respectively, compared to the reference category (0.1-2.9 g/day). In women, HR estimates did not reach statistically significance. The alcohol and PC risk association was not modified by smoking status. Findings from a large prospective study suggest that baseline and lifetime alcohol intakes were positively associated with PC risk, with more apparent risk estimates for beer and spirits/liquors than wine intake.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Bebidas Alcoólicas , Alcoolismo/complicações , Alcoolismo/epidemiologia , Dieta , Relação Dose-Resposta a Droga , Europa (Continente)/epidemiologia , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/etiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Inquéritos e Questionários
19.
Nat Commun ; 9(1): 556, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29422604

RESUMO

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


Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Bases de Dados Genéticas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fator 1-beta Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Proteínas Repressoras/genética , Tensinas/genética
20.
Int J Cancer ; 143(3): 515-526, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29473162

RESUMO

Immuno-proteomic screening has identified several tumor-associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times ≤6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited.


Assuntos
Antígenos de Neoplasias/imunologia , Autoanticorpos/imunologia , Detecção Precoce de Câncer , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/imunologia , Adulto , Idoso , Antígenos de Neoplasias/sangue , Biomarcadores Tumorais , Antígeno Ca-125 , Estudos de Casos e Controles , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Estudos Prospectivos , Fatores de Risco , Sensibilidade e Especificidade
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