| 1. |
- Haycock, Philip C., et al.
(author)
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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
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In: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
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Journal article (peer-reviewed)abstract
- IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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| 2. |
- McKay, James D., et al.
(author)
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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
- 2017
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
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Journal article (peer-reviewed)abstract
- Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
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| 3. |
- Stacey, Simon N, et al.
(author)
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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
- 2011
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:11, s. 1098-103
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Journal article (peer-reviewed)abstract
- To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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| 4. |
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| 5. |
- Ji, Xuemei, et al.
(author)
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Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
- 2018
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9, s. 1-15
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
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| 6. |
- Ji, Xuemei, et al.
(author)
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Protein-altering germline mutations implicate novel genes related to lung cancer development
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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| 7. |
- Buechner, Frederike L., et al.
(author)
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Consumption of vegetables and fruit and the risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition
- 2009
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 125:11, s. 2643-2651
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Journal article (peer-reviewed)abstract
- Previous epidemiologic studies found inconsistent associations between vegetables and fruit consumption and the risk of bladder cancer. We therefore investigated the association between vegetable and fruit consumption and the risk of bladder cancer among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Data on food consumption and complete follow-up for cancer occurrence was available for a total of 478,533 participants, who were recruited in 10 European countries. Estimates of rate ratios were obtained by Cox proportional hazard models, stratified by age at recruitment, gender and study centre, and adjusted for total energy intake, smoking status, duration of smoking and lifetime intensity of smoking. A calibration study in a subsample was used to control for dietary measurement errors. After a mean follow-up of 8.7 years, 1015 participants were newly diagnosed with bladder cancer. Increments of 100 g/day in fruit and vegetable consumption combined did not affect bladder cancer risk (i.e., calibrated HR = 0.98; 95%CI: 0.95-1.01). Borderline statistically significant lower bladder cancer risks were found among fever smokers with increased consumption of fruit and vegetables combined (HR = 0.94 95%CI: 0.87-1.00 with increments of 100 g/day; calibrate HR = 0.92 95%CI 0.79-1.06) and increased consumption of apples and pears (hard fruit; calibrated HR = 0.90 95%CI: 0.82-0.98 with increments of 25 g/day). For none of the associations a statistically significant interaction with smoking status was found. Our findings do not support an effect of fruit and vegetable consumption, combined or separately, on bladder cancer risk. (c) 2009 UICC
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| 8. |
- Crowe, Francesca L., et al.
(author)
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Dietary fat intake and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition
- 2008
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In: American Journal of Clinical Nutrition. - 1938-3207. ; 87:5, s. 1405-1413
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Journal article (peer-reviewed)abstract
- Background: Findings from early observational studies have suggested that the intake of dietary fat might be a contributing factor in the etiology of prostate cancer. However, the results from more recent prospective studies do not support this hypothesis, and the possible association between different food sources of fat and prostate cancer risk also remains unclear. Objective: The objectives were to assess whether intakes of dietary fat, subtypes of fat, and fat from animal products were associated with prostate cancer risk. Design: This was a multicenter prospective study of 142 520 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). Dietary fat intake was estimated with the use of country-specific validated food questionnaires. The association between dietary fat and risk of prostate cancer was assessed by using Cox regression, stratified by recruitment center and adjusted for height, weight, smoking, education, marital status, and energy intake. Results: After a median follow-up time of 8.7 y, prostate cancer was diagnosed in 2727 men. There was no significant association between dietary fat (total, saturated, monounsaturated, and polyunsaturated fat and the ratio of polyunsaturated to saturated fat) and risk of prostate cancer. The hazard ratio for prostate cancer for the highest versus the lowest quintile of total fat intake was 0.96 (95% CI: 0.84, 1.09; P for trend = 0.155). There were no significant associations between prostate cancer risk and fat from red meat, dairy products, and fish. Conclusion: The results from this large multicenter study suggest that there is no association between dietary fat and prostate cancer risk.
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| 9. |
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| 10. |
- Johnsen, Nina Fans, et al.
(author)
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Physical activity and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
- 2009
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 125:4, s. 902-908
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Journal article (peer-reviewed)abstract
- The evidence concerning the possible association between physical activity and the risk of prostate cancer is inconsistent and additional data are needed. We examined the association between risk of prostate cancer and physical activity at work and in leisure time in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. In our study, including 127,923 men aged 20-97 years from 8 European countries, 2,458 cases of prostate cancer were identified during 8.5 years of followup. Using the Cox proportional hazards model, we investigated the associations between prostate cancer incidence rate and occupational activity and leisure time activity in terms of participation in sports, cycling, walking and gardening; a metabolic equivalent (MET) score based on weekly time spent on the 4 activities; and a physical activity index. MET hours per week of leisure time activity, higher score in the physical activity index, participation in any of the 4 leisure time activities, and the number of leisure time activities in which the participants were active were not associated with prostate cancer incidence. However, higher level of occupational physical activity was associated with lower risk of advanced stage prostate cancer (p(trend) = 0.024). In conclusion, our data support the hypothesis of an inverse association between advanced prostate cancer risk and occupational physical activity, but we found no support for an association between prostate cancer risk and leisure time physical activity. (C) 2009 UICC
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