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.

SummaryBackgroundPublished findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.MethodsPrincipal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.FindingsDuring prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.InterpretationIf these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.FundingCancer Research UK and the Medical Research Council.

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Objective: To examine the relation between consumption of ®sh and ®sh products registered by a comprehensive food frequency questionnaire and the composition of fatty acids in serum phospholipids. Design: Cross-section study. Setting: Cardiovascular screening centre in Trondheim, Mid-Norway. Subjects: Of 256 eligible women 242 agreed to participate in the present study. Altogether 234 middle-aged women (91.4%) completed the questionnaire and gave a valid blood sample. Results: Total frequency consumption of ®sh for dinner showed only weak association with serum phospholipid fatty acid composition. In separate analyses of lean and fatty ®sh, consumption of fatty ®sh was negatively associated with n-6 and positively associated with n-3 fatty acids in serum phospholipids, while no signi®cant associations were found for lean ®sh consumption. Cod liver oil consumption was strongly related to the phospholipid fatty acid composition. The associations improved moderately when adding portion size information. Spearman's correlation coef®cient between dietary intake of eicosapentaenoic acid (EPA) and serum phospholipid EPA was 0.58, and Spearman's correlation coef®cient between intake of docosahexaenoic acid (DHA) and serum phospholipid DHA was 0.53. Conclusions: This study suggests that in populations with a high consumption of ®sh and cod liver oil, habitual intake can be re¯ected in serum phospholipids. However, as the fat content of ®sh is highly variable, separate registration of lean and fatty ®sh consumption is needed. Sponsorship: Erna and Olav Aakre's Foundation, Tromsù, and the Norwegian Cancer Society (E96071). Descriptors: ®sh; cod liver oil; n-3 fatty acids; food frequency questionnaire; serum phospholipid fatty acids.

Summary We examined the association between self-reported occupational and recreational physical activity and the subsequent risk of colorectal cancer in a population-based cohort in Norway. During a mean follow-up time of 16.3 years for males and 15.5 years for females, 236 and 99 colon cancers and 170 and 58 rectal cancers were observed in males and females, respectively, among 53 242 males and 28 274 females who attended the screening between 1972 and 1978. Physical activity at a level equivalent to walking or bicycling for at least four hours a week during leisure-time was associated with decreased risk of colon cancer among females when compared with the sedentary group (RR=0.62, 95% CI 0.40-0.97). Reduced risk of colon cancer was particularly marked in the proximal colon (RR=0.51, 95% CI 0.28-0.93). This effect was not observed for occupational physical activity alone, probably due to a narrow range of self-reported physical activity at work among females. However, by combining occupational and recreational physical activity we observed an inverse dose-response effect as increasing total activity significantly reduced colon cancer risk (P for trend=0.04). Among males 45 years or older at entry to the study, an inverse dose-response effect was observed between total physical activity and colon cancer risk (P for trend = 0.04). We also found in males a stronger preventive effect for physical activity in the proximal as compared to distal colon. In addition, we found a borderline significant decrease in colon cancer risk for occupational physical activity in males 45 years or older when compared to the sedentary group (RR = 0.74, 95% CI 0.53-1.04). All results were adjusted for age, body mass index, serum cholesterol and geographic region. No association between physical activity and rectal cancer was observed in males or females. The protective effect of physical activity on colon cancer risk is discussed in regard to energy balance, dietary factors, age, social class, body mass index and gastrointestinal transit time.Keywords: physical activity; colorectal cancer; cohort study; gender differences; subsites Cancer of the large intestine is one of the most common neoplasms in western countries (Muir et al., 1987; Engeland et al., 1993). Recently, the role of exercise in the aetiology of colon carcinogenesis has drawn particular interest. A growing number of epidemiological studies have reported a protective effect of occupational physical activity on colon cancer risk (Garabrant et al., 1984;Gerhardsson et al., 1986;Brownson et al., 1989;Peters et al., 1989;Arbman et al., 1993; Chow et al., 1993;Fraser and Pearce, 1993). Others have observed that recreational physical activity protects against colon cancer (Wu et al., 1987;Slattery et al., 1988;Gerhardsson et al., 1988;Severson et al., 1989;Ballard-Barbash et al., 1990;Lee et al., 1991;Markowitz et al., 1992; Giovannuci et al., 1995). In contrast, the association between physical activity and risk of rectal cancer is more inconsistent (Vena et al., 1985;Ge...

Western style diets and lifestyles are associated with increasing rates of obesity, diabetes and insulin resistance. Higher circulating insulin levels may modulate cell proliferation and apoptosis either directly or indirectly by increasing the bioactivity of IGF‐I and decreasing the bioactivity of some of its binding proteins. The objective of this study was to determine the association of increasing levels of serum C‐peptide, a biomarker of pancreatic insulin secretion, and IGF binding proteins (IGFBP) ‐1 and ‐2 with colorectal cancer risk in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), a large cohort involving 10 Western European countries. A total of 1,078 colorectal cancer cases were matched (age, date of blood donation, fasting status, gender, study center) to an equal number of control subjects. Relative cancer risks were estimated using conditional logistic regression models. Serum C‐peptide concentration was positively associated with an increased colorectal cancer risk for the highest versus the lowest quintile (OR = 1.56, 95% CI = 1.16–2.09, ptrend < 0.01), which was slightly attenuated after adjustment for BMI and physical activity (OR = 1.37, 95% CI = 1.00–1.88, ptrend = 0.10). When stratified by anatomical site, the cancer risk was stronger in the colon (OR = 1.67, 95% CI = 1.14–2.46, ptrend < 0.01) than in the rectum (OR = 1.42, 95% CI = 0.90–2.25, ptrend = 0.35). The cancer risk estimates were not heterogeneous by gender or fasting status. No clear colorectal cancer risk associations were observed for IGFBP‐1 or ‐2. This large prospective study confirms that hyperinsulinemia, as determined by C‐peptide levels, is associated with an increased colorectal cancer risk. © 2007 Wiley‐Liss, Inc.

The associations between recreational and occupational physical activity and the subsequent risk of prostate and testicular cancer were examined in a population-based cohort study of 53,242 men in Norway. Age at study entry was 19 to 50 years. Information on physical activity was based on questionnaire responses and a brief clinical examination. A total of 220 prostate and 47 testicular cancer cases were recorded in the Cancer Registry of Norway during a mean follow-up time of 16.3 years. We found a nonsignificant, reduced, adjusted relative risk (RR) of prostate cancer with increased level of physical activity at work and among those men with the greatest recreational physical activity. When occupational and recreational physical activity were combined, a reduced adjusted risk of prostate cancer was observed among men who walked during occupational hours and performed either moderate recreational activity (RR = 0.61, 95 percent confidence interval [CI] = 0.36 to 1.01) or regular recreational training (RR = 0.45, CI = 0.20 to 1.01) relative to sedentary men (test for trend, P = 0.03). Physically active men who were older than 60 years of age at diagnosis showed a reduced adjusted RR of borderline significance, while no association was observed for younger men. No evidence was found for any association between physical activity and testicular cancer regardless of physical activity at work and recreation.

Background: The Norwegian Women and Cancer Study (NOWAC) is a national populationbased cohort study with 102 443 women enrolled at age 30-70 y from 1991 to 1997. The present study was a methodological sub-study to assess the test-retest reproducibility of the NOWAC food frequency questionnaire (FFQ), and to study how measurement errors in the data can affect estimates of disease risk.