| 1. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 2. |
- Ward, Heather A., et al.
(författare)
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Haem iron intake and risk of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
- 2019
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Ingår i: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 0954-3007 .- 1476-5640. ; 8:73, s. 1122-1132
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk using detailed smoking history data and serum cotinine to control for potential confounding. Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 416,746 individuals from 10 countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident lung cancer (n = 3731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1489 matched controls for whom serum cotinine was available. Results: Haem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3 mg/1000 kcal 1.03, 95% CI 1.00–1.07), and in the highest versus lowest quintile (HR 1.16, 95% CI 1.02–1.32; trend across quintiles: P = 0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case–control subset. Conclusions: Greater haem iron intake may be modestly associated with lung cancer risk.
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| 3. |
- Georgiadis, Panagiotis, et al.
(författare)
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DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia
- 2019
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 126, s. 24-36
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To characterize the impact of PCB exposure on DNA methylation in peripheral blood leucocytes and to evaluate the corresponding changes in relation to possible health effects, with a focus on B-cell lymphoma.METHODS: We conducted an epigenome-wide association study on 611 adults free of diagnosed disease, living in Italy and Sweden, in whom we also measured plasma concentrations of 6 PCB congeners, DDE and hexachlorobenzene.RESULTS: We identified 650 CpG sites whose methylation correlates strongly (FDR < 0.01) with plasma concentrations of at least one PCB congener. Stronger effects were observed in males and in Sweden. This epigenetic exposure profile shows extensive and highly statistically significant overlaps with published profiles associated with the risk of future B-cell chronic lymphocytic leukemia (CLL) as well as with clinical CLL (38 and 28 CpG sites, respectively). For all these sites, the methylation changes were in the same direction for increasing exposure and for higher disease risk or clinical disease status, suggesting an etiological link between exposure and CLL. Mediation analysis reinforced the suggestion of a causal link between exposure, changes in DNA methylation and disease. Disease connectivity analysis identified multiple additional diseases associated with differentially methylated genes, including melanoma for which an etiological link with PCB exposure is established, as well as developmental and neurological diseases for which there is corresponding epidemiological evidence. Differentially methylated genes include many homeobox genes, suggesting that PCBs target stem cells. Furthermore, numerous polycomb protein target genes were hypermethylated with increasing exposure, an effect known to constitute an early marker of carcinogenesis.CONCLUSIONS: This study provides mechanistic evidence in support of a link between exposure to PCBs and the etiology of CLL and underlines the utility of omic profiling in the evaluation of the potential toxicity of environmental chemicals.
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| 4. |
- Butt, Julia, et al.
(författare)
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Antibody Responses to Fusobacterium nucleatum Proteins in Prediagnostic Blood Samples are not Associated with Risk of Developing Colorectal Cancer
- 2019
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 28:9, s. 1552-1555
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is a lack of prospective data on the potential association of Fusobacterium nucleatum (F. nucleatum) and colorectal cancer risk. In this study, we assessed whether antibody responses to F. nucleatum are associated with colorectal cancer risk in prediagnostic serum samples in the European Prospective Investigation into Nutrition and Cancer (EPIC) cohort.Methods: We applied a multiplex serology assay to simultaneously measure antibody responses to 11 F. nucleatum antigens in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI).Results: We observed neither a statistically significant colorectal cancer risk association for antibodies to individual F. nucleatum proteins nor for combined positivity to any of the 11 proteins (OR, 0.81; 95% CI, 0.62–1.06).Conclusions: Antibody responses to F. nucleatum proteins in prediagnostic serum samples from a subset of colorectal cancer cases and matched controls within the EPIC study were not associated with colorectal cancer risk.Impact: Our findings in prospectively ascertained serum samples contradict the existing literature on the association of F. nucleatum with colorectal cancer risk. Future prospective studies, specifically detecting F. nucleatum in stool or tissue biopsies, are needed to complement our findings.
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| 5. |
- Dewi, Nikmah Utami, et al.
(författare)
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Anthropometry and the risk of lung cancer in EPIC
- 2016
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 184:2, s. 129-139
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Tidskriftsartikel (refereegranskat)abstract
- The associations of body mass index (BMI) and other anthropometric measurements with lung cancer were examined in 348,108 participants in the European Investigation Into Cancer and Nutrition (EPIC) between 1992 and 2010. The study population included 2,400 case patients with incident lung cancer, and the average length of follow-up was 11 years. Hazard ratios were calculated using Cox proportional hazard models in which we modeled smoking variables with cubic splines. Overall, there was a significant inverse association between BMI (weight (kg)/height (m)2) and the risk of lung cancer after adjustment for smoking and other confounders (for BMI of 30.0-34.9 versus 18.5-25.0, hazard ratio = 0.72, 95% confidence interval: 0.62, 0.84). The strength of the association declined with increasing follow-up time. Conversely, after adjustment for BMI, waist circumference and waist-to-height ratio were significantly positively associated with lung cancer risk (for the highest category of waist circumference vs. the lowest, hazard ratio = 1.25, 95% confidence interval: 1.05, 1.50). Given the decline of the inverse association between BMI and lung cancer over time, the association is likely at least partly due to weight loss resulting from preclinical lung cancer that was present at baseline. Residual confounding by smoking could also have influenced our findings.
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| 6. |
- Gallo, Valentina, et al.
(författare)
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Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis: The EPIC cohort.
- 2013
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Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 1526-632X .- 0028-3878. ; 80:9, s. 829-838
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim of this study was to investigate for the first time the association between body fat and risk of amyotrophic lateral sclerosis (ALS) with an appropriate prospective study design. METHODS: The EPIC (European Prospective Investigation into Cancer and Nutrition) study included 518,108 individuals recruited from the general population across 10 Western European countries. At recruitment, information on lifestyle was collected and anthropometric characteristics were measured. Cox hazard models were fitted to investigate the associations between anthropometric measures and ALS mortality. RESULTS: Two hundred twenty-two ALS deaths (79 men and 143 women) occurred during the follow-up period (mean follow-up = 13 years). There was a statistically significant interaction between categories of body mass index and sex regarding ALS risk (p = 0.009): in men, a significant linear decrease of risk per unit of body mass index was observed (hazard ratio = 0.93, 95% confidence interval 0.86-0.99 per kg/m(2)); among women, the risk was more than 3-fold increased for underweight compared with normal-weight women. Among women, a significant risk reduction increasing the waist/hip ratio was also evident: women in the top quartile had less than half the risk of ALS compared with those in the bottom quartile (hazard ratio = 0.48, 95% confidence interval 0.25-0.93) with a borderline significant p value for trend across quartiles (p = 0.056). CONCLUSION: Increased prediagnostic body fat is associated with a decreased risk of ALS mortality.
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| 7. |
- Gallo, Valentina, et al.
(författare)
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Smoking and risk for amyotrophic lateral sclerosis : analysis of the EPIC cohort
- 2009
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Ingår i: Annals of Neurology. - New York : J. Wiley & Sons. - 0364-5134 .- 1531-8249. ; 65:4, s. 378-385
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Cigarette smoking has been reported as "probable" risk factor for Amyotrophic Lateral Sclerosis (ALS), a poorly understood disease in terms of aetiology. The extensive longitudinal data of the European Prospective Investigation into Cancer and Nutrition (EPIC) were used to evaluate age-specific mortality rates from ALS and the role of cigarette smoking on the risk of dying from ALS. Methods: A total of 517,890 healthy subjects were included, resulting in 4,591,325 person-years. ALS cases were ascertained through death certificates. Cox hazard models were built to investigate the role of smoking on the risk of ALS, using packs/years and smoking duration to study dose-response. Results: A total of 118 subjects died from ALS, resulting in a crude mortality rate of 2.69 per 100,000/year. Current smokers at recruitment had an almost two-fold increased risk of dying from ALS compared to never smokers (HR = 1.89, 95% C.I. 1.14-3.14), while former smokers at the time of enrollment had a 50% increased risk (HR = 1.48, 95% C.I. 0.94-2.32). The number of years spent smoking increased the risk of ALS (p for trend = 0.002). Those who smoked more than 33 years had more than a two-fold increased risk of ALS compared with never smokers (HR = 2.16, 95% C.I. 1.33-3.53). Conversely, the number of years since quitting smoking was associated with a decreased risk of ALS compared with continuing smoking. Interpretation: These results strongly support the hypothesis of a role of cigarette smoking in aetiology of ALS. We hypothesize that this could occur through lipid peroxidation via formaldehyde exposure.
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| 8. |
- Hosnijeh, Fatemeh Saberi, et al.
(författare)
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Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study
- 2014
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:12, s. 2910-2917
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Tidskriftsartikel (refereegranskat)abstract
- Recent epidemiological investigations have reported on the association between telomere length (TL) and a number of malignancies, including B-cell lymphoma (BCL). The reported results for BCLs are however inconsistent. We carried out a nested case-control study to determine whether TL is associated with future risk of BCL. Using quantitative polymerase chain reaction, the relative TL (i.e. the ratio of telomere repeat copy number to single gene copy number) was measured in mononuclear cell DNA of prediagnostic peripheral blood samples of 464 lymphoma cases and 464 matched controls (median time between blood collection and diagnosis, 4.6 years). Conditional logistic regression was used to analyze the association between TL and the risk of developing lymphoma and histologic subtypes. TL was significantly longer in cases compared to controls (p 5 0.01). Multivariable models showed a significantly increased risk of BCL [odds ratio (OR) = 1.66, 1.80 and 3.20 for quartiles 2-4, respectively, p-trend = 0.001], diffuse large B-cell lymphoma (DLBCL) (OR = 1.20, 2.48 and 2.36 for quartiles 2-4, respectively, p-trend = 0.03) and follicular lymphoma (FL) (OR = 1.39, 1.90 and 2.69 for quartiles 2-4, respectively, p-trend = 0.02) with increasing TL. This study suggests an association between longer leucocyte TL and increased risk of BCL which was most pronounced for DLBCL and FL.
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| 9. |
- Roulland, Sandrine, et al.
(författare)
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t(14;18) Translocation: A Predictive Blood Biomarker for Follicular Lymphoma
- 2014
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Ingår i: Journal of Clinical Oncology. - 1527-7755 .- 0732-183X. ; 32:13, s. 1347-1347
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of follicular lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and its relationship with progression to disease remains unclear. Here we sought to determine whether t(14;18)-positive cells in healthy individuals represent tumor precursors and whether their detection could be used as an early predictor for FL. Participants and Methods Among 520,000 healthy participants enrolled onto the EPIC (European Prospective Investigation Into Cancer and Nutrition) cohort, we identified 100 who developed FL 2 to 161 months after enrollment. Prediagnostic blood from these and 218 controls were screened for t(14;18) using sensitive polymerase chain reaction-based assays. Results were subsequently validated in an independent cohort (65 case participants; 128 controls). Clonal relationships between t(14;18) cells and FL were also assessed by molecular backtracking of paired prediagnostic blood and tumor samples. Results Clonal analysis of t(14;18) junctions in paired prediagnostic blood versus tumor samples demonstrated that progression to FL occurred from t(14;18)-positive committed precursors. Furthermore, healthy participants at enrollment who developed FL up to 15 years later showed a markedly higher t(14;18) prevalence and frequency than controls (P < .001). Altogether, we estimated a 23-fold higher risk of subsequent FL in blood samples associated with a frequency > 10(-4) (odds ratio, 23.17; 95% CI, 9.98 to 67.31; P < .001). Remarkably, risk estimates remained high and significant up to 15 years before diagnosis. Conclusion High t(14;18) frequency in blood from healthy individuals defines the first predictive biomarker for FL, effective years before diagnosis.
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| 10. |
- Sanikini, Harinakshi, et al.
(författare)
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Anthropometric and reproductive factors and risk of esophageal and gastric cancer by subtype and subsite : Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
- 2020
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 146:4, s. 929-942
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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