| 1. |
- Johansson, Mattias, et al.
(författare)
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The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study
- 2019
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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| 2. |
- Machiela, Mitchell J, et al.
(författare)
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Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.
- 2017
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 72:5, s. 747-754
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
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| 3. |
- Scelo, Ghislaine, et al.
(författare)
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Genome-wide association study identifies multiple risk loci for renal cell carcinoma.
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
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| 4. |
- Yeager, Meredith, et al.
(författare)
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Identification of a new prostate cancer susceptibility locus on chromosome 8q24.
- 2009
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:10, s. 1055-7
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. We identify a new association with prostate cancer risk on chromosome 8q24 (rs620861, P = 1.3 x 10(-10), heterozygote OR = 1.17, 95% CI 1.10-1.24; homozygote OR = 1.33, 95% CI 1.21-1.45). This defines a new locus associated with prostate cancer susceptibility on 8q24.
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| 5. |
- Berndt, Sonja I, et al.
(författare)
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Large-scale fine mapping of the HNF1B locus and prostate cancer risk
- 2011
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:16, s. 3322-3329
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10(-8) with the most significant association with rs4430796 (P = 1.62 × 10(-24)). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r(2)= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10(-23)) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10(-8)); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.
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| 6. |
- Timmins, Iain R., et al.
(författare)
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International pooled analysis of leisure-time physical activity and premenopausal breast cancer in women from 19 cohorts
- 2024
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 42:8, s. 927-939
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer.METHODS: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity.RESULTS: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship (Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity.CONCLUSION: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.
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| 7. |
- Delahaye-Sourdeix, Manon, et al.
(författare)
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A Novel Risk Locus at 6p21.3 for Epstein-Barr Virus-Positive Hodgkin Lymphoma
- 2015
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 24:12, s. 1838-1843
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein-Barr virus (EBV) status, particularly within the MHC region.METHODS: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls.RESULTS: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83-2.97; P = 7 × 10(-12)], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92-1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10(-8)). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL.CONCLUSIONS: rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL.IMPACT: This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease. Cancer Epidemiol Biomarkers Prev; 24(12); 1838-43.
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| 8. |
- Lindemann, Kristina, et al.
(författare)
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Serum lipids and endometrial cancer risk: results from the HUNT-II study.
- 2009
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Ingår i: International journal of cancer. Journal international du cancer. - : Wiley. - 1097-0215. ; 124:12, s. 2938-41
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is a major risk factor for endometrial cancer. Still, the association of obesity-related metabolic factors, such as serum lipids and lipoprotein levels, is unclear. We prospectively examined the association of serum levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein (non-HDL), and HDL cholesterol with endometrial cancer risk among 31,473 women. During 9 years of follow-up, 100 cases of endometrial cancer were identified by linkage to the Cancer Registry of Norway. There was a positive association of serum triglyceride levels with endometrial cancer risk. Comparing the highest to the lowest quartile of triglycerides, the age-adjusted hazard ratio was 2.34 (95% CI: 1.04-5.28), and further adjustment for body mass index attenuated the association (hazard ratio 1.79, 95% CI: 0.79-4.05). For total serum cholesterol, low-density lipoprotein cholesterol and HDL cholesterol there were no associations with endometrial cancer risk, either without or after adjustment for body mass index. Serum triglyceride levels were positively associated with the risk of endometrial cancer, and some of the association seems to be attributable to obesity. Apart from higher estrogen levels produced in adipose tissue, mechanisms more specifically related to triglycerides may also be involved in endometrial cancer. Further prospective studies on this subject are needed to better understand the association of blood lipids with endometrial cancer risk.
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| 9. |
- Sandvei, Marie Søfteland, et al.
(författare)
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Menopausal hormone therapy and breast cancer risk : effect modification by body mass through life
- 2019
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:3, s. 267-278
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Tidskriftsartikel (refereegranskat)abstract
- It is not known whether increased breast cancer risk caused by menopausal hormone therapy (HT) depends on body mass patterns through life. In a prospective study of 483,241 Norwegian women aged 50–69 years at baseline, 7656 women developed breast cancer during follow-up (2006–2013). We combined baseline information on recalled body mass in childhood/adolescence and current (baseline) body mass index (BMI) to construct mutually exclusive life-course body mass patterns. We assessed associations of current HT use with breast cancer risk according to baseline BMI and life-course patterns of body mass, and estimated relative excess risk due to interaction (RERI). Within all levels of baseline BMI, HT use was associated with increased risk. Considering life-course body mass patterns as a single exposure, we used women who “remained at normal weight” through life as the reference, and found that being “overweight as young” was associated with lower risk (hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.76–0.94), whereas women who “gained weight” had higher risk (HR 1.20, 95% CI 1.12–1.28). Compared to never users of HT who were “overweight as young”, HT users who either “remained at normal weight” or “gained weight” in adulthood were at higher risk than expected when adding the separate risks (RERI 0.52, 95% CI 0.09–0.95, and RERI 0.37, 95% CI − 0.07–0.80), suggesting effect modification. Thus, we found that women who remain at normal weight or gain weight in adulthood may be more susceptible to the risk increasing effect of HT compared to women who were overweight as young.
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