| 1. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 2. |
- Machiela, Mitchell J, et al.
(författare)
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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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| 3. |
- Friedenreich, Christine, et al.
(författare)
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Anthropometric factors and risk of endometrial cancer: the European prospective investigation into cancer and nutrition
- 2007
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Ingår i: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 1573-7225 .- 0957-5243. ; 18:4, s. 399-413
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Tidskriftsartikel (refereegranskat)abstract
- Objective To examine the association between anthropometry and endometrial cancer, particularly by menopausal status and exogenous hormone use subgroups. Methods Among 223,008 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, there were 567 incident endometrial cancer cases during 6.4 years of follow-up. The analysis was performed with Cox proportional hazards modeling. Results Weight, body mass index (BMI), waist and hip circumferences and waist-hip ratio (WHR) were strongly associated with increased risk of endometrial cancer. The relative risk (RR) for obese (BMI 30- < 40 kg/m(2)) compared to normal weight (BMI < 25) women was 1.78, 95% CI = 1.41-2.26, and for morbidly obese women (BMI >= 40) was 3.02, 95% CI = 1.66-5.52. The RR for women with a waist circumference of >= 88 cm vs. < 80 cm was 1.76, 95% CI = 1.42-2.19. Adult weight gain of >= 20 kg compared with stable weight (+/- 3 kg) increased risk independent of body weight at age 20 (RR = 1.75, 95% CI = 1.11-2.77). These associations were generally stronger for postmenopausal than premenopausal women, and oral contraceptives never-users than ever-users, and much stronger among never-users of hormone replacement therapy compared to ever-users. Conclusion Obesity, abdominal adiposity, and adult weight gain were strongly associated with endometrial cancer risk. These associations were particularly evident among never-users of hormone replacement therapy.
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| 4. |
- Lahmann, Petra H., et al.
(författare)
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Anthropometric measures and epithelial ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition
- 2010
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 126:10, s. 2404-2415
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Tidskriftsartikel (refereegranskat)abstract
- We examined the associations of measured anthropometric factors, including general and central adiposity and height, with ovarian cancer risk. We also investigated these associations by menopausal status and for specific histological subtypes. Among 226,798 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, there were 611 incident cases of primary, malignant, epithelial ovarian cancer diagnosed during a mean 8.9 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (as), adjusted for potential confounders. Compared to women with body mass index (BMI) < 25 kg/m(2), obesity (BMI >= 30 kg/m(2)) was associated with excess ovarian cancer risk for all women combined (HR = 1.33, 95% Cl = 1.05-1.68; p(trend) = 0.02) and postmenopausal women (HR = 1.59, 95% Cl = 1.20-2.10; p(trend) = 0.001), but the association was weaker for premenopausal women (HR = 1.16, 95% Cl = 0.65-2.06; p(trend) = 0.65). Neither height or weight gain, nor BMI-adjusted measures of fat distribution assessed by waist circumference, waist-hip ratio (WHR) or hip circumference were associated with overall risk. WHR was related to increased risk of mucinous tumors (BMI-adjusted HR per 0.05 unit increment = 1.17, 95% Cl = 1.00-1.38). For all women combined, no other significant associations with risk were observed for specific histological subtypes. This large, prospective study provides evidence that obesity is an important modifiable risk factor for epithelial ovarian cancer, particularly among postmenopausal women.
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| 5. |
- Pischon, Tobias, et al.
(författare)
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Body size and risk of colon and rectal cancer in the European prospective investigation into cancer and nutrition (EPIC)
- 2006
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 98:13, s. 920-931
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Tidskriftsartikel (refereegranskat)abstract
- Background: Body weight and body mass index (BMI) are positively related to risk of colon cancer in men, whereas weak or no associations exist in women. This discrepancy may be related to differences in fat distribution between sexes or to the use of hormone replacement therapy (HRT) in women. Methods: We used multivariable adjusted Cox proportional hazards models to examine the association between anthropometric measures and risks of colon and rectal cancer among 368 277 men and women who were free of cancer at baseline from nine countries of the European Prospective Investigation Into Cancer and Nutrition. All statistical tests were two-sided. Results: During 6.1 years of follow-up, we identified 984 and 586 patients with colon and rectal cancer, respectively. Body weight and BMI were statistically significantly associated with colon cancer risk in men (highest versus lowest quintile of BMI, relative risk [RR] = 1.55, 95% confidence interval [CI] = 1.12 to 2.15; P-trend =.006) but not in women. In contrast, comparisons of the highest to the lowest quintile showed that several anthropometric measures, including waist circumference (men, RR = 1.39,95% CI = 1.01 to 1.93; P-trend = .001; women, RR = 1.48, 95% CI = 1.08 to 2.03; P-trend =.008), waist-to-hip ratio (WHR; men, RR = 1.51, 95% CI = 1.06 to 2.15; P-trend =.006; women, RR = 1.52, 95% CI = 1.12 to 2.05; P-trend =.002), and height (men, RR = 1.40, 95% CI = 0.99 to 1.98; P-trend =.04; women, RR = 1.79, 95% CI = 1.30 to 2.46; P-trend <.001) were related to colon cancer risk in both sexes. The estimated absolute risk of developing colon cancer within 5 years was 203 and 131 cases per 100 000 men and 129 and 86 cases per 100000 women in the highest and lowest quintiles of WHR, respectively. Upon further stratification, no association of waist circumference and WHR with risk of colon cancer was observed among postmenopausal women who used HRT. None of the anthropometric measures was statistically significantly related to rectal cancer. Conclusions: Waist circumference and WHR, indicators of abdominal obesity, were strongly associated with colon cancer risk in men and women in this population. The association of abdominal obesity with colon cancer risk may vary depending on HRT use in postmenopausal women; however, these findings require confirmation in future studies.
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| 6. |
- Cust, Anne E., et al.
(författare)
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Metabolic syndrome, plasma lipid, lipoprotein and glucose levels, and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)
- 2007
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Ingår i: Endocrine-Related Cancer. - 1479-6821 .- 1351-0088. ; 14:3, s. 755-767
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Tidskriftsartikel (refereegranskat)abstract
- To clarify the role of metabolic factors in endometrial carcinogenesis, we conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), and examined the relation between prediagnostic plasma lipids, lipoproteins, and glucose, the metabolic syndrome (MetS; a cluster of metabolic factors) and endometrial cancer risk. Among pre- and postmenopausal women, 284 women developed endometrial cancer during follow-up. Using risk set sampling, 546 matched control subjects were selected. From conditional logistic regression models, high-density lipoprotein cholesterol (HDL-C) levels were inversely associated with risk body mass index (BMI)-adjusted relative risk (FR) for top versus bottom quartile 0.61 (95% confidence intervals (CI) 0.38-0.97), P-trend= 0.02). Glucose levels were positively associated with risk (BMI-adjusted RR top versus bottom quartile 1.69 (95% Cl 0.99-2.90), P-trend, = 0.03), which appeared stronger among postmenopausal women (BMI-adjusted RR top versus bottom tertile 2.61 (95% Cl 1.46-4.66), P-trend=0.0006, P-heterogeneity=0.13) and never-users of exogenous hormones (P-heterogeneity=0-005 for oral contraceptive (OC) use and 0.05 for hormone replacement therapy-use). The associations of HDL-C and glucose with risk were no longer statistically significant after further adjustment for obesity-related hormones. Plasma total cholesterol, Low-density lipoprotein cholesterol (LDL-C), and triglycerides were not significantly related to overall risk. The presence of MetS was associated with risk (RR 2.12 (95% CI 1.51-2.97)), which increased with the number of MetS factors (P-trend=0.02). An increasing number of MetS factors other than waist circumference, however, was marginally significantly associated with risk only in women with waist circumference above the median (P-interaction=0-01). None of the associations differed significantly by fasting status. These findings suggest that metabolic abnormalities and obesity may act synergistically to increase endometrial cancer risk.
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| 7. |
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| 8. |
- Brenner, Darren R, et al.
(författare)
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Leisure-time physical activity and lung cancer risk : a systematic review and meta-analysis
- 2016
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Ingår i: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 95, s. 17-27
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We conducted a systematic review and meta-analysis of the association between recreational physical activity and lung cancer risk to update previous analyses and to examine population subgroups of interest defined by smoking status and histology.MATERIALS AND METHODS: We searched the PubMed database for studies up to May 2015. Individual study characteristics were abstracted including study design, number of cases, assessment of recreational physical activity and type and level of adjustment for confounding factors. Combined effect estimates were calculated for the overall associations and across subgroups of interest.RESULTS: We identified 28 studies that were eligible for inclusion in the meta-analysis. The overall analysis indicated an inverse association between recreational physical activity and lung cancer risk (Relative Risk (RR), 0.76; 95% Confidence Interval (CI), 0.69-0.85, p-value: <0.001). Similar inverse associations with risk were also noted for all evaluated histological subtypes, including adenocarcinoma (RR, 0.80; 95% CI, 0.72-0.88), squamous (RR, 0.80; 95% CI, 0.71-0.90) and small cell (RR, 0.79; 95% CI, 0.66-0.94). When we examined effects by smoking status, inverse associations between recreational physical activity and lung cancer risk were observed among former (RR, 0.77; 95% CI, 0.69-0.85) and current smokers (RR, 0.77; 95% CI, 0.72-0.83), but not among never smokers (RR, 0.96; 95% CI, 0.79-1.18).CONCLUSION: Results from this meta-analysis suggest that regular recreational physical activity may be associated with reduced risk of lung cancer. Only four studies examining never smokers were identified, suggesting the need for additional research in this population.
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