Incidence of prostate, colorectal and male breast cancers in relation with statins and testosterone replacement therapy: SEER-Medicare 2007-2015.

INTRODUCTION: Statins and testosterone replacement therapy (TTh) have been inconsistently associated with a reduced risk of hormone-related cancers (HRCs, prostate [PCa], colorectal [CRC], and male breast cancers [BrCa]). Yet, the joint association of statins and TTh with the incidence of these cancers, and whether these associations vary by race, remains poorly understood. The objective of this retrospective cohort study is to examine the independent and joint effects of pre-diagnostic use of statins and TTh on the risk of HRCs, including PCa, CRC, and male BrCa. MATERIALS: and Methods: In 105,690 men (≥65 yrs) identified using the SEER-Medicare 2007-2015 data, we identified 82,578 White and 10,256 Black men. Pre-diagnostic prescription of statins and TTh was ascertained for this analysis and categorized into four groups (Neither users, statins alone, TTh alone and Dual users). Multivariable Time-varying Cox proportional hazards and Accelerated Failure Time (AFT) models were performed. RESULTS: We found inverse joint associations of statins and TTh with incident HRCs before (aHR: 0.39; 95 % CI: 0.35-0.44) and after 3 years of follow-up (aHR: 0.74; 95 % CI: 0.67-0.82). This included a lower risk for advanced stage HRC (only <3 years follow-up). Similar joint associations were identified with incident PCa, aggressive PCa, incident CRC, and its specific right- and left-sided CRC (only <3 years follow-up). In general, the inverse associations persisted among White (mainly <3 years follow-up) and Black men (high-grade HRC and <3 years follow-up). Findings from the AFT analysis were similar. DISCUSSION: Pre-diagnostic use of statins and TTh were, independently and jointly, associated with reduced risks of HRC and specific cancer sites at three years of follow-up overall, and among White and Black men. Greatest associations of HRCs risk reduction were observed among dual users (statins plus TTh). Further studies are needed to validate these findings, including larger samples of Black men, and male BrCa sites.

Adiposity assessed close to diagnosis and prostate cancer prognosis in the EPIC study.

BACKGROUND: Adiposity has been characterised as a modifiable risk factor of prostate cancer. Its association with outcomes after prostate cancer diagnosis, however, needs to be better understood and obtain more evidence to assist the development of lifestyle guidance for prostate cancer patients. METHODS: We investigated the associations between adiposity indices close to prostate cancer diagnosis (up to two years pre- or up to five years post-diagnosis) and mortality in 1,968 men of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Men were followed for a median of 9.5 years. Cox proportional-hazards models were adjusted for age and year of diagnosis, stage, grade, smoking and stratified by country. RESULTS: Each 5-unit increment in pre- or post-diagnosis body mass index (BMI) combined was associated with a 30% higher rate of all-cause and a 49% higher rate of prostate cancer-specific mortality. Similarly, each 5-unit increment in pre-diagnosis BMI was associated with a 35% higher rate of all-cause and a 51% higher rate of prostate cancer-specific mortality. The associations were less strong for post-diagnosis BMI with a lower number of men in analyses. Less clear positive associations were shown for waist circumference, hip circumference, and waist-to-hip ratio but data was limited. CONCLUSIONS: Elevated levels of adiposity close to prostate cancer diagnosis could lead to higher risk of mortality; therefore, men are encouraged to maintain a healthy weight. Additional research is needed to confirm if excessive adiposity after prostate cancer diagnosis could worsen prognosis.

Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing.

BACKGROUND: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer. OBJECTIVE: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing. DESIGN: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-ß, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors. RESULTS: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways. CONCLUSIONS: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.

Identifying proteomic risk factors for overall, aggressive, and early onset prostate cancer using Mendelian Randomisation and tumour spatial transcriptomics.

BACKGROUND: Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. METHODS: We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis-pQTL Mendelian randomisation (MR) and colocalisation. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalisation were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate-specific tissue expression were additionally investigated using spatial transcriptomic data in prostate tumour tissue to assess their role in tumour aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets. FINDINGS: We identified 20 proteins genetically linked to prostate cancer risk (14 for overall [8 specific], 7 for aggressive [3 specific], and 8 for early onset disease [2 specific]), of which the majority replicated where data were available. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54-2.93], PYY [OR = 1.87, 95% CI: 1.43-2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73-0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99-4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67-0.86] and TPM3 [OR = 0.47, 95% CI: 0.34-0.64]. We confirmed an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80-0.82], and also found an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82-0.86] and early onset disease [OR = 0.71, 95% CI: 0.68-0.74]. Using spatial transcriptomics data, we identified MSMB as the genome-wide top-most predictive gene to distinguish benign regions from high grade cancer regions that comparatively had five-fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk also mapped to existing therapeutic interventions. INTERPRETATION: Our findings emphasise the importance of proteomics for improving our understanding of prostate cancer aetiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added benefit of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumours. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer. FUNDING: This work was supported by Cancer Research UK (grant no. C8221/A29017).

The dietary changes during Ramadan and their impact on anthropometry, blood pressure, and metabolic profile.

Background: The effect of Ramadan intermittent fasting (RIF) on the metabolic profile, anthropometry and blood pressure has been investigated in multiple studies. However, it is still unknown to what extent changes in nutrient intakes contribute to these changes. Methods: This observational study was conducted in London (UK) in 2019. The study collected diverse data from a community-based sample in London before and during/after Ramadan. Collected data included a 3-day food diary (before and during Ramadan), as well as blood samples, anthropometric measurements and blood pressure (before and after Ramadan). The food diary was translated into nutritional data using nutrition software "Nutritics." The changes in nutrient intakes were investigated using a mixed-effects regression model. The impact of adjusting for nutrient intake change was investigated on the absolute difference of metabolites (Nightingale platform), systolic/diastolic blood pressure and anthropometric measures. Results: The study collected data on food intake before and during Ramadan from 56 participants; the mean age was 44.7 ± 17.3, and 51.8% (n = 29) were females. We found a change in the intake of 11 nutritional factors, glucose, fructose, betaine, sugars, sugars as monosaccharide equivalents, lutein/zeaxanthin, starch, starch as monosaccharide equivalents, proline, glutamic acid and lycopene. No changes in quantities or proportions of macronutrients, carbohydrates, protein and fat. Mainly, the changes in diet during Ramadan are characterized by more consumption of sugars (62%, p < 0.001) and a lower intake of starch (-21%, p = 0.012). The changes in 14 metabolite levels (two glycolysis-related metabolites, one amino acid, two ketone bodies, two triglyceride, six lipoprotein subclasses, and an inflammation marker) after Ramadan were partially associated with some changes in nutrient intakes during Ramadan, especially betaine, fructose, glucose, starches and sugars. The lutein/zeaxanthin intake change explained inversely 14% of systolic blood pressure changes. Moreover, BMI and weight changes were partially explained by changes in intake of fat (7%; 9%), monounsaturated fat (6%; 7%), starch (8%; 9%), and starch as monosaccharide equivalents (8%; 9%) intakes in a direct relationship. Conclusion: Diet changes during Ramadan were associated partially with the observed changes in the metabolic profile, blood pressure and anthropometry. This confirms the changes associated with RIF in the metabolic profile, blood pressure and anthropometry are not an absolute physiological response to the diet transition occurring during Ramadan.

Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.

BACKGROUND: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. METHODS: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. FINDINGS: The 3-DF joint test revealed two significant loci with p-value <5 × 10-8. Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10-3) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10-7). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10-8) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029). INTERPRETATION: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings. FUNDING: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments.

Identification of potential mediators of the relationship between body mass index and colorectal cancer: a Mendelian randomization analysis.

BACKGROUND: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. METHODS: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. RESULTS: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. CONCLUSIONS: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.

Post-diagnosis adiposity, physical activity, sedentary behaviour, dietary factors, supplement use and colorectal cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading.

Based on the World Cancer Research Fund Global Cancer Update Programme, we performed systematic reviews and meta-analyses to investigate the association of post-diagnosis adiposity, physical activity, sedentary behaviour, and dietary factors with colorectal cancer prognosis. We searched PubMed and Embase until 28th February, 2022. An independent expert committee and expert panel graded the quality of evidence. A total of 167 unique publications were reviewed, and all but five were observational studies. The quality of the evidence was graded conservatively due to the high risk of several biases. There was evidence of non-linearity in the associations between body mass index and colorectal cancer prognosis. The associations appeared reverse J-shaped, and the quality of this evidence was graded as limited (likelihood of causality: limited-no conclusion). The evidence on recreational physical activity and lower risk of all-cause mortality (relative risk [RR] highest vs. lowest: 0.69, 95% confidence interval [CI]: 0.62-0.77) and recurrence/disease-free survival (RR: 0.80, 95% CI: 0.70-0.92) was graded as limited-suggestive. There was limited-suggestive evidence for the associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), intake of whole grains and coffee with lower risk of all-cause mortality, and between unhealthy dietary patterns and intake of sugary drinks with higher risk of all-cause mortality. The evidence for other exposures on colorectal cancer outcomes was sparse and graded as limited-no conclusion. Analyses were conducted excluding cancer patients with metastases without substantial changes in the findings. Well-designed intervention and cohort studies are needed to support the development of lifestyle recommendations for colorectal cancer patients.

Post-diagnosis physical activity and sedentary behaviour and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

Low physical activity and high sedentary behaviour have been clearly linked with colorectal cancer development, yet data on their potential role in colorectal cancer survival is limited. Better characterisation of these relationships is needed for the development of post-diagnosis physical activity and sedentary behaviour guidance for colorectal cancer survivors. We searched PubMed and Embase through 28 February 2022 for studies assessing post-diagnosis physical activity, and/or sedentary behaviour in relation to all-cause and cause-specific mortality and recurrence after colorectal cancer diagnosis. Total and recreational physical activity were assessed overall and by frequency, duration, intensity, and volume using categorical, linear, and non-linear dose-response random-effects meta-analyses. The Global Cancer Update Programme (CUP Global) independent Expert Committee on Cancer Survivorship and Expert Panel interpreted and graded the likelihood of causality. We identified 16 observational studies on 82,220 non-overlapping patients from six countries. Physical activity was consistently inversely associated with colorectal cancer morbidity and mortality outcomes, with 13%-60% estimated reductions in risk. Sedentary behaviour was positively associated with all-cause mortality. The evidence had methodological limitations including potential confounding, selection bias and reverse causation, coupled with a limited number of studies for most associations. The CUP Global Expert panel concluded limited-suggestive evidence for recreational physical activity with all-cause mortality and cancer recurrence. Total physical activity and its specific domains and dimensions, and sedentary behaviour were all graded as limited-no conclusion for all outcomes. Future research should focus on randomised trials, while observational studies should obtain objective and repeated physical activity measures and better adjustment for confounders.

Post-diagnosis dietary factors, supplement use and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

The role of diet in colorectal cancer prognosis is not well understood and specific lifestyle recommendations are lacking. We searched for randomised controlled trials (RCTs) and longitudinal observational studies on post-diagnosis dietary factors, supplement use and colorectal cancer survival outcomes in PubMed and Embase from inception until 28th February 2022. Random-effects dose-response meta-analyses were conducted when at least three studies had sufficient information. The evidence was interpreted and graded by the CUP Global independent Expert Committee on Cancer Survivorship and Expert Panel. Five RCTs and 35 observational studies were included (30,242 cases, over 8700 all-cause and 2100 colorectal cancer deaths, 3700 progression, recurrence, or disease-free events). Meta-analyses, including 3-10 observational studies each, were conducted for: whole grains, nuts/peanuts, red and processed meat, dairy products, sugary drinks, artificially sweetened beverages, coffee, alcohol, dietary glycaemic load/index, insulin load/index, marine omega-3 polyunsaturated fatty acids, supplemental calcium, circulating 25-hydroxyvitamin D (25[OH]D) and all-cause mortality; for alcohol, supplemental calcium, circulating 25(OH)D and colorectal cancer-specific mortality; and for circulating 25(OH)D and recurrence/disease-free survival. The overall evidence was graded as 'limited'. The inverse associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), whole grains, total, caffeinated, or decaffeinated coffee and all-cause mortality and the positive associations between unhealthy dietary patterns, sugary drinks and all-cause mortality provided 'limited-suggestive' evidence. All other exposure-outcome associations provided 'limited-no conclusion' evidence. Additional, well-conducted cohort studies and carefully designed RCTs are needed to develop specific lifestyle recommendations for colorectal cancer survivors.

Post-diagnosis adiposity and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

The adiposity influence on colorectal cancer prognosis remains poorly characterised. We performed a systematic review and meta-analysis on post-diagnosis adiposity measures (body mass index [BMI], waist circumference, waist-to-hip ratio, weight) or their changes and colorectal cancer outcomes. PubMed and Embase were searched through 28 February 2022. Random-effects meta-analyses were conducted when at least three studies had sufficient information. The quality of evidence was interpreted and graded by the Global Cancer Update Programme (CUP Global) independent Expert Committee on Cancer Survivorship and Expert Panel. We reviewed 124 observational studies (85 publications). Meta-analyses were possible for BMI and all-cause mortality, colorectal cancer-specific mortality, and cancer recurrence/disease-free survival. Non-linear meta-analysis indicated a reverse J-shaped association between BMI and colorectal cancer outcomes (nadir at BMI 28 kg/m2). The highest risk, relative to the nadir, was observed at both ends of the BMI distribution (18 and 38 kg/m2), namely 60% and 23% higher risk for all-cause mortality; 95% and 26% for colorectal cancer-specific mortality; and 37% and 24% for cancer recurrence/disease-free survival, respectively. The higher risk with low BMI was attenuated in secondary analyses of RCTs (compared to cohort studies), among studies with longer follow-up, and in women suggesting potential methodological limitations and/or altered physiological state. Descriptively synthesised studies on other adiposity-outcome associations of interest were limited in number and methodological quality. All the associations were graded as limited (likelihood of causality: no conclusion) due to potential methodological limitations (reverse causation, confounding, selection bias). Additional well-designed observational studies and interventional trials are needed to provide further clarification.

Prospective associations of leucocyte subtypes and obesity with the risk of developing cutaneous malignant melanoma in the UK Biobank cohort.

BACKGROUND: Obesity is associated with chronic low-grade inflammation, which is linked to cancer development. Abdominal obesity (a body mass index, ABSI), however, has unusually been associated inversely with cutaneous malignant melanoma (CMM), while general obesity (body mass index, BMI) is associated positively. Leucocytes participate in inflammation and are higher in obesity, but prospective associations of leucocytes with cutaneous malignant melanoma are unclear. METHODS: We examined the prospective associations of neutrophil, lymphocyte, and monocyte counts (each individually), as well as the prospective associations of ABSI and BMI, with cutaneous malignant melanoma in UK Biobank. We used multivariable Cox proportional hazards models and explored heterogeneity according to sex, menopausal status, age (≥ 50 years at recruitment), smoking status, ABSI (dichotomised at the median: ≥73.5 women; ≥79.8 men), BMI (normal weight, overweight, obese), and time to diagnosis. RESULTS: During a mean follow-up of 10.2 years, 2174 CMM cases were ascertained in 398,450 participants. There was little evidence for associations with neutrophil or lymphocyte counts. Monocyte count, however, was associated inversely in participants overall (HR = 0.928; 95%CI: 0.888-0.971; per one standard deviation increase; SD = 0.144*109/L women; SD = 0.169*109/L men), specifically in older participants (HR = 0.906; 95%CI: 0.862-0.951), and more clearly in participants with low ABSI (HR = 0.880; 95%CI: 0.824-0.939), or with BMI ≥ 25 kg/m2 (HR = 0.895; 95%CI: 0.837-0.958 for overweight; HR = 0.923; 95%CI: 0.848-1.005 for obese). ABSI was associated inversely in pre-menopausal women (HR = 0.810; 95%CI: 0.702-0.935; SD = 4.95) and men (HR = 0.925; 95%CI: 0.867-0.986; SD = 4.11). BMI was associated positively in men (HR = 1.148; 95%CI: 1.078-1.222; SD = 4.04 kg/m2). There was little evidence for heterogeneity according to smoking status. The associations with monocyte count and BMI were retained to at least 8 years prior to diagnosis, but the association with ABSI was observed up to 4 years prior to diagnosis and not for longer follow-up time. CONCLUSIONS: Monocyte count is associated prospectively inversely with the risk of developing CMM in older individuals, while BMI is associated positively in men, suggesting a mechanistic involvement of factors related to monocytes and subcutaneous adipose tissue in melanoma development. An inverse association with ABSI closer to diagnosis may reflect reverse causality or glucocorticoid resistance.

Evaluating the impact of pre-diagnostic use of statins and testosterone replacement therapy on mortality outcomes in older men with hormone-related cancers: Surveillance, Epidemiology, and End Results-Medicare 2007-2015.

BACKGROUND: The link between the pre-diagnostic use of statins and testosterone replacement therapy and their impact on hormone-related cancers, prostate cancer, colorectal cancer, and male breast cancer survival remains a topic of controversy. Further, there is a knowledge gap concerning the joint effects of statins and testosterone replacement therapy on hormone-related cancer survival outcomes. OBJECTIVE: To examine the independent and joint effects of pre-diagnostic use of statins and testosterone replacement therapy on the risk of all-cause and cause-specific mortality among older men diagnosed with hormone-related cancers, including prostate cancer, colorectal cancer, and male breast cancer. METHODS: In 41,707 men (≥65 years) of Surveillance, Epidemiology, and End Results-Medicare 2007-2015, we identified 31,097 prostate cancer, 10,315 colorectal cancer, and 295 male breast cancer cases. Pre-diagnostic prescription of statins and testosterone replacement therapy was ascertained and categorized into four groups (Neither users, statins alone, testosterone replacement therapy alone, and Dual users). Multivariable-adjusted Cox proportional hazards and competing-risks (Fine-Gray subdistribution hazard) models were conducted. RESULTS: No significant associations were found in Cox-proportional hazard models for hormone-related cancers. However, in the Fine-Gray competing risk models among high-grade hormone-related cancers, statins alone had an 11% reduced risk of hormone-related cancer-specific death (hazard ratio: 0.89; 95% confidence interval: 0.81-0.99; p 0.0451). In the prostate cancer cohort with both statistical models, the use of testosterone replacement therapy alone had a 24% lower risk of all-cause death (hazard ratio: 0.76; 95% confidence interval: 0.59-0.97; p 0.0325) and a 57% lower risk of prostate cancer-specific death (hazard ratio: 0.43; 95% confidence interval: 0.24-0.75; p 0.0029). Similar inverse associations were found among aggressive prostate cancer cases with testosterone replacement therapy alone and statins alone. No significant associations were found in the colorectal cancer and male breast cancer sub-groups. CONCLUSION: Pre-diagnostic use of statins and testosterone replacement therapy showed a survival benefit with reduced mortality in high-grade hormone-related cancer patients (only statins) and aggressive prostate cancer patients in both statistical models. Findings of testosterone replacement therapy use in aggressive prostate cancer settings could facilitate clinical trials. Further studies with extended follow-up periods are needed to substantiate these findings.

Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses.

BACKGROUND: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. METHODS: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). FINDINGS: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10-5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10-5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). INTERPRETATION: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). FUNDING: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

Metabolomics of Ramadan fasting and associated risk of chronic diseases.

BACKGROUND: The dramatic change in lifestyle associated with Ramadan fasting raises questions about its effect on metabolism and health. Metabolites, as the end product of metabolism, are excellent candidates to be studied in this regard. OBJECTIVE: This study aims to investigate the effect of Ramadan fasting on the metabolic profile and risk of chronic diseases. METHODS: The London Ramadan study (LORANS) is an observational study in which 2 blood samples were collected from 72 participants a few days before and after the fasting month of Ramadan. We conducted metabolomic profiling using nuclear magnetic resonance spectroscopy to assess the change in individual metabolites from before to after Ramadan. Also, we generated metabolic scores (scaled from 0 to 100) for 7 chronic diseases in the UK Biobank and assessed the association of Ramadan fasting with these scores in LORANS. RESULTS: Of the 72 participants, 35 were male (48.6%); the mean (± standard deviation) age was 45.7 (±16) y. Ramadan fasting was associated with changes in 14 metabolites (1 inflammation marker, 1 amino acid, 2 glycolysis-related metabolites, 2 ketone bodies, 2 triglyceride, and 6 lipoprotein subclasses), independent of changes in body composition. Using data from 117,981 participants in the UK Biobank, we generated metabolic scores for diabetes, hypertension, coronary artery disease, renal failure, colorectal cancer, breast cancer, and lung cancer. The metabolic scores for lung cancer, colorectal cancer, and breast cancer were lower after Ramadan in LORANS (-4.74, 9.6%, 95% confidence interval -6.56, -2.91, P < 0.001), (-1.09, -2.4%, -1.69, -0. 50, P < 0.001), and (-0.48, -1.1%, -0. 81, -0.15, P = 0.006), respectively. CONCLUSIONS: Ramadan fasting is associated with short-term favorable changes in the metabolic profile concerning risk of some chronic diseases. These findings should be further investigated in future, larger studies of longer follow-up with clinical outcomes.

Links between the genetic determinants of morning plasma cortisol and body shape: a two-sample Mendelian randomisation study.

High cortisol production in Cushing's syndrome leads to fat centralisation. The influence of modest cortisol variations on body shape, however, is less clear. We examined potentially causal associations between morning plasma cortisol and body shape and obesity with inverse-variance weighted random-effects models in a two-sample Mendelian randomisation analysis. We used publicly available summary statistics from the CORtisol NETwork (CORNET) consortium, UK Biobank, and the Genetic Investigation of Anthropometric Traits (GIANT) consortium. Only in women, morning plasma cortisol (proxied by ten genetic polymorphisms) was associated positively with waist size reflected in waist-to-hip index (WHI, 0.035 standard deviation (SD) units change per one SD cortisol increase; 95% confidence interval (0.002-0.067); p = 0.036) and "a body shape index" (ABSI; 0.039 (0.006-0.071); p = 0.021). There was no evidence for associations with hip index (HI) or body mass index (BMI). Among individual polymorphisms, rs7450600 stood out (chromosome 6; Long Intergenic Non-Protein-Coding RNA 473 gene, LINC00473). Morning plasma cortisol proxied by rs7450600 was associated positively with WHI and inversely with HI and BMI in women and men. Our findings support a causal association of higher morning plasma cortisol with larger waist size in women and highlight LINC00473 as a genetic link between morning plasma cortisol and body shape.

Interactions of obesity, body shape, diabetes and sex steroids with respect to prostate cancer risk in the UK Biobank cohort.

BACKGROUND: Obesity and diabetes are associated inversely with low-grade prostate cancer risk and affect steroid hormone synthesis but whether they modify each other's impact on prostate cancer risk remains unknown. METHODS: We examined the independent associations of diabetes, body mass index (BMI), 'a body shape index' (ABSI), hip index (HI), circulating testosterone, sex hormone binding globulin (SHBG) (per one standard deviation increase) and oestradiol ≥175 pmol/L with total prostate cancer risk using multivariable Cox proportional hazards models for UK Biobank men. We evaluated multiplicative interactions (pMI ) and additive interactions (relative excess risk from interaction (pRERI ), attributable proportion (pAR ), synergy index (pSI )) with obese (BMI ≥30 kg/m2 ) and diabetes. RESULTS: During a mean follow-up of 10.3 years, 9417 incident prostate cancers were diagnosed in 195,813 men. Diabetes and BMI were associated more strongly inversely with prostate cancer risk when occurring together (pMI = 0.0003, pRERI = 0.032, pAP = 0.020, pSI = 0.002). ABSI was associated positively in obese men (HR = 1.081; 95% CI = 1.030-1.135) and men with diabetes (HR = 1.114; 95% CI = 1.021-1.216). The inverse associations with obesity and diabetes were attenuated for high-ABSI ≥79.8 (pMI = 0.022, pRERI = 0.008, pAP = 0.005, pSI <0.0001 obesity; pMI = 0.017, pRERI = 0.047, pAP = 0.025, pSI = 0.0005 diabetes). HI was associated inversely in men overall (HR = 0.967; 95% CI = 0.947-0.988). Free testosterone (FT) was associated most strongly positively in normal weight men (HR = 1.098; 95% CI = 1.045-1.153) and men with diabetes (HR = 1.189; 95% CI = 1.081-1.308). Oestradiol was associated inversely in obese men (HR = 0.805; 95% CI = 0.682-0.951). The inverse association with obesity was stronger for high-FT ≥243 pmol/L (pRERI = 0.040, pAP = 0.031, pSI = 0.002) and high-oestradiol (pRERI = 0.030, pAP = 0.012, pSI <0.0001). The inverse association with diabetes was attenuated for high-FT (pMI = 0.008, pRERI = 0.015, pAP = 0.009, pSI = 0.0006). SHBG was associated inversely in men overall (HR = 0.918; 95% CI = 0.895-0.941), more strongly for high-HI ≥49.1 (pMI = 0.024). CONCLUSIONS: Obesity and diabetes showed synergistic inverse associations with prostate cancer risk, likely involving testosterone reduction for diabetes and oestrogen generation for obesity, which were attenuated for high-ABSI. HI and SHBG showed synergistic inverse associations with prostate cancer risk.

Sleep Quality and Cognitive Abilities in the Greek Cohort of Epirus Health Study.

Purpose: Sleep is essential to all human body functions as well as brain functions. Inadequate sleep quantity and poor sleep quality have been shown to directly affect cognitive functioning and especially memory. The primary aim of the present study was to investigate the association of sleep quality with cognitive abilities cross-sectionally in a middle-aged Greek population and secondarily to examine this association prospectively in a smaller group of these participants. Patients and Methods: A total of 2112 healthy adults aged 25-70 years (mean: 46.7±11.5) from the Epirus Health Study cohort were included in the analysis and 312 of them participated in secondary prospective analysis. Sleep quality was measured by the Pittsburgh Sleep Quality Index (PSQI) scale and cognition was assessed in primary cross-sectional analyses with three neuropsychological tests, namely the Verbal Fluency test, the Logical Memory test and the Trail Making test, and in secondary prospective analyses with online versions of Posner cueing task, an emotional recognition task, the Corsi block-tapping task and the Stroop task. Statistical analysis was performed using multivariable linear regression models adjusted for age, sex, education, body mass index and alcohol consumption. Results: Attention/processing speed was the only cognitive domain associated cross-sectionally with PSQI score. Specifically, participants with better self-reported sleep quality performed faster on the Trail Making Test - Part A (ß= 0.272 seconds, 95% CI 0.052, 0.493). Conclusion: Further studies are needed to clarify the association of sleep quality with cognition, especially in middle-aged people that are still in productive working years.

Allometric versus traditional body-shape indices and risk of colorectal cancer: a Mendelian randomization analysis.

BACKGROUND: Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing. METHODS: We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia. RESULTS: WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03-1.39) and in women (1.15, 1.06-1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03-1.57; and 1.40, 1.10-1.77, respectively), and with colon cancer in women (1.20, 1.07-1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women. CONCLUSIONS: This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI.

Multiple long-term conditions in people with psoriasis: a latent class and bidirectional Mendelian randomization analysis.

BACKGROUND: Coexisting long-term conditions (LTCs) in psoriasis and their potential causal associations with the disease are not well -established. OBJECTIVES: To determine distinct clusters of LTCs in people with psoriasis and the potential bidirectional causal association between these LTCs and psoriasis. METHODS: Using latent class analysis, cross-sectional data from people with psoriasis from the UK Biobank were analysed to identify distinct psoriasis-related comorbidity profiles. Linkage disequilibrium score regression (LDSR) was applied to compute the genetic correlation between psoriasis and LTCs. Two-sample bidirectional Mendelian randomization (MR) analysis assessed the potential causal direction using independent genetic variants that reached genome-wide significance (P < 5 × 10-8). RESULTS: Five comorbidity clusters were identified in a population of 10 873 people with psoriasis. LDSR revealed that psoriasis was positively genetically correlated with heart failure [genetic correlation (rg) = 0.23, P = 8.8 × 10-8], depression (rg = 0.12, P = 2.7 × 10-5), coronary artery disease (CAD; rg = 0.15, P = 2 × 10-4) and type 2 diabetes (rg = 0.19, P = 3 × 10-3). Genetic liability to CAD was associated with an increased risk of psoriasis [inverse variance weighted (IVW) odds ratio (ORIVW) 1.159, 95% confidence interval (CI) 1.055-1.274; P = 2 × 10-3]. The MR pleiotropy residual sum and outlier (MR-PRESSO; ORMR-PRESSO 1.13, 95% CI 1.042-1.228; P = 6 × 10-3) and the MR-robust adjusted profile score (RAPS) (ORMR-RAPS 1.149, 95% CI 1.062-1.242; P = 5 × 10-4) approaches corroborate the IVW findings. The weighted median (WM) generated similar and consistent effect estimates but was not statistically significant (ORWM 1.076, 95% CI 0.949-1.221; P = 0.25). Evidence for a suggestive increased risk was detected for CAD (ORIVW 1.031, 95% CI 1.003-1.059; P = 0.03) and heart failure (ORIVW 1.019, 95% CI 1.005-1.033; P = 9 × 10-3) in those with a genetic liability to psoriasis; however, MR sensitivity analyses did not reach statistical significance. CONCLUSIONS: Five distinct clusters of psoriasis comorbidities were observed with these findings to offer opportunities for an integrated approach to comorbidity prevention and treatment. Coexisting LTCs share with psoriasis common genetic and nongenetic risk factors, and aggressive lifestyle modification in these people is anticipated to have an impact beyond psoriasis risk. Genetically predicted CAD is possibly associated with an increased risk of psoriasis, altering our prior knowledge.