Circulating 25-Hydroxyvitamin D Concentration and Risk of Breast, Prostate, and Colorectal Cancers: The Melbourne Collaborative Cohort Study.

BACKGROUND: The role of vitamin D in cancer risk remains controversial, and limited data exist on associations between vitamin D and subtypes of specific cancers. We investigated associations between circulating 25-hydroxyvitamin D (25(OH)D) and risk of colorectal, breast, and prostate cancers, including subtypes. METHODS: A case-cohort study within the Melbourne Collaborative Cohort Study included 547 colorectal, 634 breast, and 824 prostate cancers, and a sex-stratified random sample of participants (n = 2,996). Concentration of 25(OH)D in baseline-dried blood spots was measured using LC-MS/MS. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for each cancer in relation to plasma-equivalent 25(OH)D concentration. Associations by stage and BRAF/KRAS status for colorectal cancer, estrogen receptor status for breast cancer, and aggressiveness for prostate cancer were examined in competing risks models. RESULTS: 25(OH)D concentrations were inversely associated with risk of colorectal cancer [highest vs. lowest 25(OH)D quintile: HR, 0.71; 95% confidence interval (CI), 0.51-0.98], which was limited to women (HR, 0.52; 95% CI, 0.33-0.82). Circulating 25(OH)D was also inversely associated with BRAF V600E-positive colorectal cancer (per 25 nmol/L increment: HR, 0.71; 95% CI, 0.50-1.01). There were no inverse associations with breast cancer (HR, 0.98; 95% CI, 0.70-1.36) or prostate cancer (HR, 1.11; 95% CI, 0.82-1.48). CONCLUSIONS: Circulating 25(OH)D concentration was inversely associated with colorectal cancer risk for women, but not with risk of breast cancer or prostate cancer. IMPACT: Vitamin D might play a role in preventing colorectal cancer. Further studies are required to confirm whether vitamin D is associated with specific tumor subtypes

Circulating 25-hydroxyvitamin D concentration and cause-specific mortality in the Melbourne Collaborative Cohort Study.

Vitamin D deficiency is associated with higher all-cause mortality, but associations with specific causes of death are unclear. We investigated the association between circulating 25-hydroxyvitamin D (25(OH)D) concentration and cause-specific mortality using a case-cohort study within the Melbourne Collaborative Cohort Study (MCCS). Eligibility for the case-cohort study was restricted to participants with baseline dried blood spot samples and no pre-baseline diagnosis of cancer. These analyses included participants who died (n = 2307) during a mean follow-up of 14 years and a sex-stratified random sample of eligible cohort participants ('subcohort', n = 2923). Concentration of 25(OH)D was measured using liquid chromatography-tandem mass spectrometry. Cox regression, with Barlow weights and robust standard errors to account for the case-cohort design, was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cause-specific mortality in relation to 25(OH)D concentration with adjustment for confounders. Circulating 25(OH)D concentration was inversely associated with risk of death due to cancer (HR per 25 nmol/L increment = 0.88, 95 % CI 0.78-0.99), particularly colorectal cancer (HR = 0.75, 95 % CI 0.57-0.99). Higher 25(OH)D concentrations were also associated with a lower risk of death due to diseases of the respiratory system (HR = 0.62, 95 % CI 0.43-0.88), particularly chronic obstructive pulmonary disease (HR = 0.53, 95 % CI 0.30-0.94), and diseases of the digestive system (HR = 0.44, 95 % CI 0.26-0.76). Estimates for diabetes mortality (HR = 0.64, 95 % CI 0.33-1.26) and cardiovascular disease mortality (HR = 0.90, 95 % CI 0.76-1.07) lacked precision. The findings suggest that vitamin D might be important for preventing death due to some cancers, respiratory diseases, and digestive diseases

Long-term weight change and risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Background: The role of obesity and weight change in breast-cancer development is complex and incompletely understood. We investigated long-term weight change and breast-cancer risk by body mass index (BMI) at age 20 years, menopausal status, hormone replacement therapy (HRT) and hormone-receptor status. Methods: Using data on weight collected at three different time points from women who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we investigated the association between weight change from age 20 years until middle adulthood and risk of breast cancer. Results: In total, 150 257 women with a median age of 51 years at cohort entry were followed for an average of 14 years (standard deviation = 3.9) during which 6532 breast-cancer cases occurred. Compared with women with stable weight (+/- 2.5 kg), long-term weight gain >10 kg was positively associated with postmenopausal breast-cancer risk in women who were lean at age 20 [hazard ratio (HR) = 1.42; 95% confidence interval 1.22-1.65] in ever HRT users (HR = 1.23; 1.04-1.44), in never HRT users (HR = 1.40; 1.16-1.68) and in oestrogen-and-progesterone-receptor-positive (ERthornPRthorn) breast cancer (HR = 1.46; 1.15-1.85). Conclusion: Long-term weight gain was positively associated with postmenopausal breast cancer in women who were lean at age 20, both in HRT ever users and non-users, and hormone-receptor-positive breast cancer

Mycotoxin Exposure and Renal Cell Carcinoma Risk: An Association Study in the EPIC European Cohort

Background: Mycotoxins have been suggested to contribute to a spectrum of adverse health effects in humans, including at low concentrations. The recognition of these food contaminants being carcinogenic, as co-occurring rather than as singularly present, has emerged from recent research. The aim of this study was to assess the potential associations of single and multiple mycotoxin exposures with renal cell carcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: Food questionnaire data from the EPIC cohort were matched to mycotoxin food occurrence data compiled by the European Food Safety Authority (EFSA) from European Member States to assess long-term dietary mycotoxin exposures, and to associate these with the risk of renal cell carcinoma (RCC, n = 911 cases) in 450,112 EPIC participants. Potential confounding factors were taken into account. Analyses were conducted using Cox's proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) with mycotoxin exposures expressed as mu g/kg body weight/day. Results: Demographic characteristics differed between the RCC cases and non-cases for body mass index, age, alcohol intake at recruitment, and other dietary factors. In addition, the mycotoxin exposure distributions showed that a large proportion of the EPIC population was exposed to some of the main mycotoxins present in European foods such as deoxynivalenol (DON) and derivatives, fumonisins, Fusarium toxins, Alternaria toxins, and total mycotoxins. Nevertheless, no statistically significant associations were observed between the studied mycotoxins and mycotoxin groups, and the risk of RCC development. Conclusions: These results show an absence of statistically significant associations between long-term dietary mycotoxin exposures and RCC risk. However, these results need to be validated in other cohorts and preferably using repeated dietary exposure measurements. In addition, more occurrence data of, e.g., citrinin and fumonisins in different food commodities and countries in the EFSA database are a prerequisite to establish a greater degree of certainty

Association between circulating 25-hydroxyvitamin D concentrations and hip replacement for osteoarthritis: a prospective cohort study

BACKGROUND: To examine the association between circulating 25(OH)D concentrations and incidence of total hip replacement for osteoarthritis in a prospective cohort study. METHODS: This study examined a random sample of 2651 participants in the Melbourne Collaborative Cohort Study who had 25(OH)D concentrations measured from dried blood spots collected in 1990-1994. Participants who underwent total hip replacement for osteoarthritis between January 2001 and December 2018 were identified by linking the cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of total hip replacement for osteoarthritis in relation to 25(OH)D concentrations, adjusted for confounders. RESULTS: Eighty-six men and eighty-seven women had a total hip replacement for osteoarthritis. Compared with men in the lowest (1st) quartile of 25(OH)D concentration, the HR for total hip replacement was 2.32 (95% CI 1.05, 5.13) for those in the 2nd quartile, 2.77 (95% CI 1.28, 6.00) for those in the 3rd quartile, and 1.73 (95% CI 0.75, 4.02) for those in the highest quartile of 25(OH)D concentrations (p for trend 0.02). There was little evidence of an association in women. CONCLUSIONS: Higher circulating 25(OH)D concentrations were associated with an increased risk of total hip replacement for osteoarthritis in men but not in women. Although the underlying mechanism warrants further investigation, our findings highlight the need to determine the optimal levels of circulating 25(OH)D to reduce the risk of hip osteoarthritis

Assessment of the EarlyCDT-Lung test as an early biomarker of lung cancer in ever-smokers: A retrospective nested case-control study in two prospective cohorts

The EarlyCDT-Lung test is a blood-based autoantibody assay intended to identify high-risk individuals for low-dose computed tomography lung cancer screening. However, there is a paucity of evidence on the performance of the EarlyCDT-Lung test in ever-smokers. We conducted a nested case-control study within two prospective cohorts to evaluate the risk-discriminatory performance of the EarlyCDT-Lung test using prediagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a prediagnostic blood sample <3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT-Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT-Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI: 0.34-2.30) for a moderate risk EarlyCDT-Lung test result and 1.09 (95% CI: 0.48-2.47) for a high-risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI: 4.6-14) and overall specificity was 92% (95% CI: 87-96) when considering a high-risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI: 7.2-32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT-Lung test in identifying the high-risk subjects in ever-smokers for lung cancer screening in the EPIC and NSHDS cohorts

Diet and BMI Correlate with Metabolite Patterns Associated with Aggressive Prostate Cancer

Three metabolite patterns have previously shown prospective inverse associations with the risk of aggressive prostate cancer within the European Prospective Investigation into Cancer and Nutrition (EPIC). Here, we investigated dietary and lifestyle correlates of these three prostate cancer-related metabolite patterns, which included: 64 phosphatidylcholines and three hydroxysphingomyelins (Pattern 1), acylcarnitines C18:1 and C18:2, glutamate, ornithine, and taurine (Pattern 2), and 8 lysophosphatidylcholines (Pattern 3). In a two-stage cross-sectional discovery (n = 2524) and validation (n = 518) design containing 3042 men free of cancer in EPIC, we estimated the associations of 24 dietary and lifestyle variables with each pattern and the contributing individual metabolites. Associations statistically significant after both correction for multiple testing (False Discovery Rate = 0.05) in the discovery set and at p < 0.05 in the validation set were considered robust. Intakes of alcohol, total fish products, and its subsets total fish and lean fish were positively associated with Pattern 1. Body mass index (BMI) was positively associated with Pattern 2, which appeared to be driven by a strong positive BMI-glutamate association. Finally, both BMI and fatty fish were inversely associated with Pattern 3. In conclusion, these results indicate associations of fish and its subtypes, alcohol, and BMI with metabolite patterns that are inversely associated with risk of aggressive prostate cancer

Reproductive and hormonal factors and risk of renal cell carcinoma among women in the European Prospective Investigation into Cancer and Nutrition

PurposeThe incidence of small intestinal cancer (SIC) is increasing, however, its aetiology remains unclear due to a lack of data from large-scale prospective cohorts. We examined modifiable risk factors in relation to SIC overall and by histological subtype.MethodsWe analysed 450,107 participants enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. Cox proportional hazards models were used to estimate univariable and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsDuring an average of 14.1 years of follow-up, 160 incident SICs (62 carcinoids, 51 adenocarcinomas) were identified. Whilst univariable models revealed a positive association for current versus never smokers and SIC (HR, 95% CI: 1.77, 1.21-2.60), this association attenuated in multivariable models. In energy-adjusted models, there was an inverse association across vegetable intake tertiles for SIC overall (HRT3vsT1, 95% CI: 0.48, 0.32-0.71, p-trend: < 0.001) and for carcinoids (HRT3vsT1, 95% CI: 0.44, 0.24-0.82, p-trend: 0.01); however, these attenuated in multivariable models. Total fat was also inversely associated with total SIC and both subtypes but only in the second tertile (SIC univariable HRT2vsT1, 95% CI: 0.57, 0.38-0.84; SIC multivariable HRT2vsT1, 95% CI: 0.55, 0.37-0.81). Physical activity, intake of alcohol, red or processed meat, dairy products, or fibre were not associated with SIC.ConclusionThese exploratory analyses found limited evidence for a role of modifiable risk factors in SIC aetiology. However, sample size was limited, particularly for histologic subtypes; therefore, larger studies are needed to delineate these associations and robustly identify risk factors for SIC

Reproductive and hormonal factors and risk of renal cell carcinoma among women in the European Prospective Investigation into Cancer and Nutrition

Background - Renal cell carcinoma (RCC) is twice as common among men compared with women, and hormonal factors have been suggested to partially explain this difference. There is currently little evidence on the roles of reproductive and hormonal risk factors in RCC aetiology. Materials & Methods - We investigated associations of age at menarche and age at menopause, pregnancy-related factors, hysterectomy and ovariectomy and exogenous hormone use with RCC risk among 298,042 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Results - During 15 years of follow-up, 438 RCC cases were identified. Parous women had higher rates of RCC compared with nulliparous women (HR = 1.71, 95% CI 1.18, 2.46), and women who were older at age of first pregnancy had lower rates of RCC (30 years + vs. Conclusion - Our results suggest that parity and reproductive organ surgeries may play a role in RCC aetiology

Metabolically-Defined Body Size Phenotypes and Risk of Endometrial Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Background: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. Methods: The association of metabolically defined body size phenotypes with endometrial cancer risk was investigated in a nested case-control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH; _1st tertile) status among the control participants. These metabolic health definitions were combined with normal weight (NW); body mass index (BMI)_25 kg/m2 or WC >_80 cm or WHR >_0. 8) status, generating four phenotype groups for each anthropometric measure: (i) MH/NW, (ii) MH/OW, (iii) MU/ NW, and (iv) MU/OW. Results: In a multivariable-adjusted conditional logistic regression model, compared with MH/NW individuals, endometrial cancer risk was higher among those classified as MU/NW [ORWC, 1.48; 95% confidence interval (CI), 1.05-2.10 and ORWHR, 1.68; 95% CI, 1.21- 2.35] and MU/OW (ORBMI, 2.38; 95% CI, 1.73-3.27; ORWC, 2.69; 95% CI, 1.92-3.77 and ORWHR, 1.83; 95% CI, 1.32-2.54). MH/OW individuals were also at increased endometrial cancer risk compared with MH/NW individuals (ORWC, 1.94; 95% CI, 1.24-3.04). Conclusions: Women with metabolic dysfunction appear to have higher risk of endometrial cancer regardless of their body size. However, OW status raises endometrial cancer risk even among women with lower insulin levels, suggesting that obesity related pathways are relevant for the development of this cancer beyond insulin. Impact: Classifying women by metabolic health may be of greater utility in identifying those at higher risk for endometrial cancer than anthropometry per se