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- Sampson, Joshua N., et al.
(author)
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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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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Journal article (peer-reviewed)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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- Assi, N., et al.
(author)
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A treelet transform analysis to relate nutrient patterns to the risk of hormonal receptor-defined breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)
- 2016
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In: Public Health Nutrition. - 1368-9800 .- 1475-2727. ; 19:2, s. 242-254
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Journal article (peer-reviewed)abstract
- Copyright © The Authors 2015 Objective: Pattern analysis has emerged as a tool to depict the role of multiple nutrients/foods in relation to health outcomes. The present study aimed at extracting nutrient patterns with respect to breast cancer (BC) aetiology. Design: Nutrient patterns were derived with treelet transform (TT) and related to BC risk. TT was applied to twenty-three log-transformed nutrient densities from dietary questionnaires. Hazard ratios (HR) and 95 % confidence intervals computed using Cox proportional hazards models quantified the association between quintiles of nutrient pattern scores and risk of overall BC, and by hormonal receptor and menopausal status. Principal component analysis was applied for comparison. Setting: The European Prospective Investigation into Cancer and Nutrition (EPIC). Subjects: Women (n 334 850) from the EPIC study. Results: The first TT component (TC1) highlighted a pattern rich in nutrients found in animal foods loading on cholesterol, protein, retinol, vitamins B12 and D, while the second TT component (TC2) reflected a diet rich in β-carotene, riboflavin, thiamin, vitamins C and B6, fibre, Fe, Ca, K, Mg, P and folate. While TC1 was not associated with BC risk, TC2 was inversely associated with BC risk overall (HRQ5 v. Q1=0·89, 95 % CI 0·83, 0·95, P trend<0·01) and showed a significantly lower risk in oestrogen receptor-positive (HRQ5 v. Q1=0·89, 95 % CI 0·81, 0·98, P trend=0·02) and progesterone receptor-positive tumours (HRQ5 v. Q1=0·87, 95 % CI 0·77, 0·98, P trend<0·01). Conclusions: TT produces readily interpretable sparse components explaining similar amounts of variation as principal component analysis. Our results suggest that participants with a nutrient pattern high in micronutrients found in vegetables, fruits and cereals had a lower risk of BC.
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- Brand, J. S., et al.
(author)
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Diabetes and onset of natural menopause : results from the European Prospective Investigation into Cancer and Nutrition
- 2015
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In: Human Reproduction. - : Oxford University Press. - 0268-1161 .- 1460-2350. ; 30:6, s. 1491-1498
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Journal article (peer-reviewed)abstract
- STUDY QUESTION: Do women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes? SUMMARY ANSWER: Although there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause. WHAT IS KNOWN ALREADY: Today, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health. STUDY DESIGN, SIZE, DURATION: We investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Determinant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01, <10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM. LIMITATIONS, REASONS FOR CAUTION: Strengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association.
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- Brand, J. S., et al.
(author)
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Diabetes and Onset of Natural Menopause : Results From the European Prospective Investigation Into Cancer and Nutrition EDITORIAL COMMENT
- 2015
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In: Obstetrical and Gynecological Survey. - 0029-7828 .- 1533-9866. ; 70:8, s. 507-508
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Journal article (other academic/artistic)abstract
- The age at natural menopause (ANM) in the Western world ranges from 40 to 60 years, with an average onset of 51 years. The exact mechanisms underlying the timing of ANM are not completely understood. Both genetic and environmental factors are involved. The best-established environmental factor affecting ANM is smoking; menopause occurs 1 to 2 years earlier in smokers. In addition to genetic and environmental factors, chronic metabolic diseases may influence ANM. Some evidence suggests that diabetes may accelerate menopausal onset. With more women of childbearing age receiving a diagnosis of diabetes, it is important to examine the impact of diabetes on reproductive health. This study was designed to determine whether ANM occurs at an earlier age among women who have diabetes before menopause than in women without diabetes. Data were obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a large multicenter prospective cohort study investigating the relationship between diet, lifestyle, and genetic factors and the incidence of cancer and other chronic diseases. A cohort of 519,978 men and women, mostly aged 27 to 70 years, were recruited primarily from the general population between 1992 and 2000. A total of 367,331 women participated in the EPIC study. After exclusions, 258,898 of these women met study inclusion criteria. Diabetes status at baseline and menopausal age were based on self-report and were obtained through questionnaires. Participants were asked if they had ever been diagnosed with diabetes and if so at what age. Associations of diabetes and age at diabetes diagnosis with ANM were estimated using time-dependent Cox regression analyses, with stratification by center and adjustments for age, smoking, reproductive, and known diabetes risk factors including smoking and with age from birth to menopause or censoring as the underlying time scale. Overall, there was no statistically significant lower risk of becoming menopausal among women with diabetes than women with no diabetes; the hazard ratio (HR) was 0.94, with a 95% confidence interval (CI) of 0.89 to 1.01. However, compared with women with no diabetes, women with diabetes before the age of 20 years had an earlier menopause (10-20 years [HR, 1.43; 95% CI, 1.02-2.01] and <10 years [HR, 1.59; 95% CI, 1.03-2.43]), whereas women with diabetes at age 50 years or older had a later menopause (HR, 0.81; 95% CI, 0.70-0.95). No association with ANM was found for diabetes onset between the ages 20 and 50 years. Strengths of the study include its large sample size and the measurement of a broad set of potential confounders. However, there were several limitations. First, results may have been underestimated because of survival bias. Second, the sequence of menopause and diabetes in women with a late age at diabetes is uncertain, as both events occur in a short period, and both diabetes and menopause status were based on self-report, not verified by medical records. Third, no distinction was made between types 1 and 2 diabetes. Although there is no overall association between diabetes and age at menopause, the data suggest that early-onset diabetes may accelerate menopause. The delaying effect of late-onset diabetes on ANM is not in agreement with other studies suggesting the opposite association.
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- Idahl, Annika, 1965-, et al.
(author)
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Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk : results from the EPIC cohort
- 2019
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In: International Journal of Gynecological Cancer. - : BMJ Publishing Group Ltd. - 1048-891X .- 1525-1438. ; 29, s. A473-A474
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Journal article (other academic/artistic)abstract
- Introduction/Background Sexually transmitted infections (STI) and pelvic inflammatory disease may cause damage to the fallopian tube where a substantial proportion of epithelial ovarian cancer (EOC) likely arises. The aim of this study was to determine whether Chlamydia trachomatis antibodies are associated with higher EOC risk. As secondary objectives, we investigated Mycoplasma genitalium,herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 and EOC risk.Methodology In a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort,791 cases and 1,669 matched controls with pre-diagnosis blood samples were analyzed. Cases and controls were matched on study center, and at blood collection age, time of day, fasting status, exogenous hormone use, menopausal status, and menstrual cycle phase. Antibodies against C. trachomatis, M. genitalium, HSV-2, and HPV 16, 18 and 45 (E6, E7, L1) were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals [CI] comparing women with positive vs. negative serology.Results A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but was associated with higher risk of the mucinous histotype (RR=2.56 [95% CI=1.3–5.05]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1), produced during persistent infection, was associated with higher risk of EOC overall (1.33 [1.09–1.62]) and of the serous subtype (1.42 [1.09–1.84]). None of the other evaluated STIs were associated with EOC risk overall; in analyses by histotype, HSV-2 was associated with higher risk of endometrioid EOC (2.93 [1.50–5.74]).Conclusion C. trachomatis infection may influence carcinogenesis of serous and mucinous EOC, while HSV-2 might promote endometrioid disease. Mechanisms linking STIs to EOC need to be further elucidated.
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| 10. |
- Li, K., et al.
(author)
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An epidemiologic risk prediction model for ovarian cancer in Europe : the EPIC study
- 2015
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 112:7, s. 1257-1265
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Journal article (peer-reviewed)abstract
- Background: Ovarian cancer has a high case-fatality ratio, largely due to late diagnosis. Epidemiologic risk prediction models could help identify women at increased risk who may benefit from targeted prevention measures, such as screening or chemopreventive agents. Methods: We built an ovarian cancer risk prediction model with epidemiologic risk factors from 202 206 women in the European Prospective Investigation into Cancer and Nutrition study. Results: Older age at menopause, longer duration of hormone replacement therapy, and higher body mass index were included as increasing ovarian cancer risk, whereas unilateral ovariectomy, longer duration of oral contraceptive use, and higher number of full-term pregnancies were decreasing risk. The discriminatory power (overall concordance index) of this model, as examined with five-fold cross-validation, was 0.64 (95% confidence interval (CI): 0.57, 0.70). The ratio of the expected to observed number of ovarian cancer cases occurring in the first 5 years of follow-up was 0.90 (293 out of 324, 95% CI: 0.81-1.01), in general there was no evidence for miscalibration. Conclusion: Our ovarian cancer risk model containing only epidemiological data showed modest discriminatory power for a Western European population. Future studies should consider adding informative biomarkers to possibly improve the predictive ability of the model.
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