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Background Case reports Conclusion Equine Coronavirus (ECoV) can cause gastrointestinal disease and was first described in 2000 in the USA followed by several international outbreak case reports. Disease manifestation is characterised by vague clinical signs, including mild pyrexia, lethargy and anorexia. Morbidity ranges greatly from 10% to 83%. Although uncommon, ECoV may result in death secondary to disruption to the gastrointestinal barrier causing endotoxaemia and hyperammonaemic encephalopathy. Unfortunately to date, there is no vaccine available to prevent ECoV.Three faecal quantitative polymerase chain reaction (qPCR)‐positive ECoV cases are described that presented with mild to severe colic signs: a 2‐year‐old Miniature Pony gelding from South Australia, an 8‐year‐old Arabian Riding Pony gelding, and a 6‐year‐old Warmblood mare, both from Western Australia. The diagnosis was based on a positive faecal qPCR, which is currently the gold standard diagnostic tool. All horses in this case series survived after medical management. The Miniature Pony presented with anorexia and mild colic signs. On day 5, the pony revealed severe colic signs unresponsive to analgesia along with severe abdominal distension secondary to caecal distension requiring surgical intervention.To the authors' knowledge, this case series is the first published report of ECoV cases in Australia, and it adds both to the clinical description of the disease in horses and to the differential diagnosis list of colic signs. [ABSTRACT FROM AUTHOR]

Purpose: Macronutrient intakes vary across people and economic status, leading to a disparity in diet-related metabolic diseases. This study aimed to provide insight into this by: (1) identifying dietary patterns in adults using reduced rank regression (RRR), with macronutrients as response variables, and (2) investigating the associations between economic status and macronutrient based dietary patterns, and between dietary patterns with central obesity (waist circumference) and systemic inflammation (C-reactive protein [CRP])., Methods: 41,849 US participants from the National Health and Nutrition Examination Survey (NHANES), 1999-2018 were included. The percentages of energy from protein, carbohydrates, saturated fats, and unsaturated fats were used as response variables in RRR. Multivariable generalized linear models with Gaussian distribution were employed to investigate the associations., Results: Four dietary patterns were identified. Economic status was positively associated with both the high fat, low carbohydrate [β HighVsLow  = 0.22; 95% CI: 0.16, 0.28] and high protein patterns [β HighVsLow  = 0.07; 95% CI: 0.03, 0.11], and negatively associated with both the high saturated fat [β HighVsLow = -0.06; 95% CI: -0.08, -0.03] and the low alcohol patterns [β HighVsLow = -0.08; 95% CI; -0.10, -0.06]. The high saturated fat pattern was positively associated with waist circumference [β Q5VsQ1  = 1.71; 95% CI: 0.97, 2.44] and CRP [β Q5VsQ1  = 0.37; 95% CI: 0.26, 0.47]., Conclusion: Macronutrient dietary patterns, which varied by economic status and were associated with metabolic health markers, may explain associations between economic status and health., (© 2024. The Author(s).)

Evidence suggests that inflammation may be associated with a higher risk of endometrial cancer, but previous reviews have typically examined a limited number of biomarkers. This study aimed to critically appraise the evidence on the effect of 13 circulating inflammatory biomarkers on endometrial cancer risk. MEDLINE and EMBASE databases were searched for prospective cohort, (nested) case-control and case-cohort studies, and Mendelian randomization (MR) studies published up to 31 March 2023. We performed a random-effects meta-analysis to estimate the pooled risk ratio and 95 % confidence interval (CI) for the association between each biomarker and endometrial cancer risk. Heterogeneity between studies was assessed using the I 2 statistic. Eight studies were included in the meta-analysis. Comparing groups with the highest versus lowest concentration of biomarker, adiponectin levels were inversely associated with risk of endometrial cancer (risk ratio (RR) =0.75, 95 % CI: 0.57-0.99, I2: 9 %). Higher levels of CRP (RR=1.18, 95 % CI: 1.05-1.33, I 2 : 2 %) and TNF-α (RR=1.58, 95 % CI: 1.13-2.21, I 2 : 0 %) were positively associated with risk of endometrial cancer. There was suggestive evidence for a positive association was also found for IL-6 (RR=1.29, 95 % CI: 0.88-1.88, I 2 : 0 %) and leptin (RR=1.50, 95 % CI: 0.83-2.71, I 2 : 0 %). Our findings suggest that circulating inflammatory biomarkers are likely involved in the carcinogenesis of endometrial cancer. Future studies should consider prospective or MR design and measure a wider range of inflammatory markers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brigid M Lynch reports administrative support was provided by Cancer Council Victoria. Brigid M Lynch reports a relationship with Australasian Epidemiological Association that includes: board membership. Brigid M Lynch serves as an Associate Editor for Cancer Epidemiology If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Whether blood lipids are causally associated with colorectal cancer (CRC) risk remains unclear., Methods: Using two-sample Mendelian randomisation (MR), our study examined the associations of genetically-predicted blood concentrations of lipids and lipoproteins (primary: LDL-C, HDL-C, triglycerides, and total cholesterol), and genetically-proxied inhibition of HMGCR, NPC1L1, and PCSK9 (which mimic therapeutic effects of LDL-lowering drugs), with risks of CRC and its subsites. Genetic associations with lipids were obtained from the Global Lipids Genetics Consortium (n = 1,320,016), while genetic associations with CRC were obtained from the largest existing CRC consortium (n = 58,221 cases and 67,694 controls). Our main analysis was a multivariable MR (MVMR) with mutual adjustments for LDL-C, HDL-C, and triglycerides. Secondary analyses, including MVMR additionally-adjusting for BMI or diabetes, were also performed., Results: Genetically-predicted LDL-C was positively associated with CRC risk in the MVMR adjusted for HDL-C and triglycerides (OR = 1.09; 95%CI 1.02-1.16 per SD increase) and additionally-adjusted for BMI (OR = 1.12; 95%CI 1.05-1.21) or diabetes (OR = 1.09; 95%CI 1.02-1.17). Associations were generally consistent across anatomical subsites. No clear evidence of association was found for other lipids, lipoproteins, or LDL-lowering drug-targets., Conclusions: We found evidence of a weak positive association between LDL-C and CRC that did not appear to be explained by potential pleiotropic pathways such as via HDL-C, triglycerides, BMI, or diabetes., Competing Interests: Competing interests: DG is employed part-time by Novo Nordisk, unrelated to the submitted work. Other authors have no competing interests to declare. Ethics approval: Our study uses only publicly-available summary data from previously published studies., (© 2024. The Author(s).)

Epigenetic age quantifies biological age using DNA methylation information and is a potential pathway by which physical activity benefits general health. We aimed to assess the cross-sectional and longitudinal associations between physical activity and epigenetic age in middle-aged and older Australians. Blood DNA methylation data for 6208 participants (40% female) in the Melbourne Collaborative Cohort Study (MCCS) were available at baseline (1990-1994, mean age, 59 years) and, of those, for 1009 at follow-up (2003-2007, mean age, 69 years). Physical activity measurements (weighted scores at baseline and follow-up and total MET hours per week at follow-up) were calculated from self-reported questionnaire data. Five blood methylation-based markers of ageing (PCGrimAge, PCPhenoAge, bAge, DNAmFitAge, and DunedinPACE) and four fitness-related markers (DNAmGaitspeed, DNAmGripmax, DNAmVO2max, and DNAmFEV1) were calculated and adjusted for age. Linear regression was used to examine the cross-sectional and longitudinal associations between physical activity and epigenetic age. Effect modification by age, sex, and BMI was assessed. At baseline, a standard deviation (SD) increment in physical activity was associated with 0.03-SD (DNAmFitAge, 95%CI = 0.01, 0.06, P = 0.02) to 0.07-SD (bAge, 95%CI = 0.04, 0.09, P = 2 × 10 -8 ) lower epigenetic age. These associations were attenuated after adjustment for other lifestyle variables. Only weak evidence was found for the longitudinal association (N = 1009) of changes in physical activity and epigenetic age (e.g. DNAmFitAge: adjusted β =  - 0.04, 95%CI =  - 0.08, 0.01). The associations were not modified by age, sex, or BMI. In middle-aged and older Australians, higher levels of self-reported physical activity were associated with slightly lower epigenetic age., (© 2024. The Author(s).)

Background: Allogeneic stem cell transplantation (allo-SCT) is an efficacious treatment for hematologic malignancies but can be complicated by cardiac dysfunction and exercise intolerance impacting quality of life and longevity. We conducted a randomized controlled trial testing whether a multicomponent activity intervention could attenuate reductions in cardiorespiratory fitness and exercise cardiac function (co-primary end points) in adults undergoing allo-SCT., Methods: Sixty-two adults scheduled for allo-SCT were randomized to a 4-month activity program (n=30) or usual care (UC; n=32). Activity comprised multicomponent exercise training (3 days/week) and sedentary time reduction (≥30 min/day) program and was delivered throughout hospitalization (≈4 weeks) and for 12 weeks after discharge. Physiological assessments conducted before admission and at 12 weeks after discharge included cardiopulmonary exercise testing to quantify peak oxygen uptake ([Formula: see text]), exercise cardiac magnetic resonance imaging for peak cardiac volume (CI peak ) and stroke volume (SVI peak ) index, echocardiography-derived left ventricular ejection fraction and global longitudinal strain, and cardiac biomarkers (cTn-I [troponin-I] and BNP [B-type natriuretic peptide])., Results: Fifty-two participants (84%) completed follow-up (25 activity and 27 UC); median (interquartile range [IQR]) adherence to the activity program was 74% (41-96%). There was a marked decline in [Formula: see text] in the UC program (-3.4 mL‧kg -1 ‧min -1 [95% CI, -4.9 to -1.8]) that was attenuated with activity (-0.9 mL‧kg -1‧ min -1 [95% CI, -2.5 to 0.8]; interaction P =0.029). Activity preserved exercise cardiac function, with preservation of CI peak (0.30 L‧min -1 ‧m - 2 [95% CI, -0.34 to 0.41]) and SVI peak (0.6 mL/m 2 [95% CI, -1.3 to 2.5]), both of which declined with UC (CI peak , -0.68 L‧min -1 ‧m - 2 [95% CI, -1.3 to -0.32]; interaction P =0.008; SVI peak , -2.7 mL/m 2 [95% CI, -4.6 to -0.9]; interaction P= 0.014). There were no treatment effects of activity on cardiac biomarkers or echocardiographic indices., Conclusions: Multicomponent activity intervention during and after allo-SCT is beneficial for preserving patient cardiorespiratory fitness and exercise cardiac function. These results may have important implications for cardiovascular morbidity and mortality after allo-SCT., Registration: URL: https://anzctr.org.au/; Unique identifier: ACTRN12619000741189.

Background: Physical activity and sedentary behavior are associated with health outcomes. However, evidence may be affected by confounding bias. This study aimed to examine the relationships of physical activity and television (TV) viewing time with all-cause, cardiovascular, and cancer mortality in a cohort of Australian adults, and determine the robustness of these relationships to residual and unmeasured confounding., Methods: Data from 27,317 Melbourne Collaborative Cohort Study participants (mean age = 66) were used. Physical activity was assessed using the International Physical Activity Questionnaire-Short Form and categorized as insufficient, sufficient, or more than sufficient. TV viewing time was categorized as low, moderate, or high. Multivariable Cox regression models were used to evaluate associations of interest. E-values were calculated to assess the strength of unmeasured confounders required to negate the observed results., Results: For highest versus lowest physical activity category, the hazard ratio was 0.67 (95% confidence interval, 0.56-0.81) for all-cause mortality; E-values ranged between 1.79 and 2.44. Results were similar for cardiovascular mortality; however, hazard ratios were lower (0.72; 95% confidence interval, 0.51-1.01) and E-values much smaller (1.00-2.12) for cancer mortality. For highest versus lowest TV viewing time category, the hazard ratio was 1.08 (1.01-1.15) for all-cause mortality; E-values ranged between 1.00 and 1.37. Results were similar for cardiovascular and cancer mortality., Conclusions: Physical activity and TV viewing time were associated with mortality. The robustness to unmeasured/residual confounding was moderate for physical activity (all-cause and cardiovascular mortality), but weaker for physical activity (cancer mortality) and TV viewing time in this study of Australian adults.

The incidence of colorectal cancer (CRC) among individuals under age 50, or early-onset CRC (EOCRC), has been rising over the past few decades for unclear reasons, and the etiology of the disease remains largely unknown. Known genetic risk factors do not explain this increase, pointing to possible environmental and as-yet unidentified genetic contributors and their interactions. Previous research linked genetic variation on chromosome 6 to increased CRC risk. This region harbors multiple immune genes, including the gene encoding Major Histocompatibility Complex (MHC) class I polypeptide-related sequence A (MICA). MICA is a polygenic ligand for the Natural Killer Group 2D receptor (NKG2D), a receptor expressed on Natural Killer (NK) cells and other lymphocytes. Given that intra-tumoral NK cell infiltration correlates with favorable CRC outcomes, we hypothesized that germline genetic variation in MICA could influence CRC risk. In a discovery set of 40,125 cases and controls, we show that the minor G allele at Chr6:31373718C>G (hg19) is associated with increased risk for CRC (odds ratio (OR) = 1.09, 95% confidence interval (CI) 1.04 - 1.15, p = 0.0009). The effect is stronger in EOCRC (OR = 1.26, 95% CI 1.08 - 1.44, p = 0.0023) than in those 50 and over (OR = 1.07, 95% CI 1.02 - 1.13; p = 0.012) (Ratio of ORs = 1.32, 95% CI 1.14 - 1.52, p = 0.0002). In an independent validation set of 77,983 cases and controls, the adjusted interaction by age-of-onset was significant at OR = 1.15 (95% CI 1.03 - 1.34, p = 0.0150) with a higher risk in EOCRC. Expression quantitative trait locus analysis in normal colonic epithelia showed that MICA RNA expression decreases linearly with each additional copy of the minor G allele (p = 3.345 × 10e-18). Bulk RNA analysis of the tumor immune microenvironment revealed that tumors from patients with CG or GG genotypes have lower resting and activated NK cell infiltration as compared to tumors from patients with CC genotype. Multiplex immunofluorescence analysis demonstrated that patients with a G allele (i.e. CG or GG genotype, but not CC genotype) have a statistically significant decrease in the number of NK cells in tumor compared to adjacent normal colonic mucosa. Taken together, population-based epidemiologic, molecular, genetic, cellular and immunologic evidence demonstrate that MICA genotype is associated with increased risk of EOCRC and reduced number of NK cells in colorectal tumors, suggesting that patients with a G allele have altered NK cell-mediated immunosurveillance. These novel findings suggest that EOCRC may have a previously unrecognized innate immune-mediated etiology which merits further investigation.

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-β, 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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We assessed: (1) the independent and joint association of obstructive sleep apnea risk and healthy lifestyle with common consequences (excessive daytime sleepiness, depression, cardiovascular disease and stroke) of obstructive sleep apnea; and (2) the effect of healthy lifestyle on survival in people with increased obstructive sleep apnea risk. Data from 13,694 adults (median age 46 years; 50% men) were used for cross-sectional and survival analyses (mortality over 15 years). A healthy lifestyle score with values from 0 (most unhealthy) to 5 (most healthy) was determined based on diet, alcohol intake, physical activity, smoking and body mass index. In the cross-sectional analysis, obstructive sleep apnea risk was positively associated with all chronic conditions and excessive daytime sleepiness in a dose-response manner (p for trend < 0.001). The healthy lifestyle was inversely associated with all chronic conditions (p for trend < 0.001) but not with excessive daytime sleepiness (p for trend = 0.379). Higher healthy lifestyle score was also associated with reduced odds of depression and cardiovascular disease. We found an inverse relationship between healthy lifestyle score with depression (p for trend < 0.001), cardiovascular disease (p for trend = 0.003) and stroke (p for trend = 0.025) among those who had high obstructive sleep apnea risk. In the survival analysis, we found an inverse association between healthy lifestyle and all-cause mortality for all categories of obstructive sleep apnea risk (moderate/high- and high-risk groups [p for trend < 0.001]). This study emphasises the crucial role of a healthy lifestyle in mitigating the effects of obstructive sleep apnea risk in individuals with an elevated obstructive sleep apnea risk., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Background: Performing physical activity may provide analgesic benefit, although this effect is more established for noncancer pain rather than cancer pain. The relationship between physical activity and pain outcomes in adults with and without a history of cancer was examined., Methods: Totals of 51,439 adults without a cancer history and 10,651 adults with a cancer history from the Cancer Prevention Study II Nutrition Cohort were included. Exposures included self-reported moderate to vigorous physical activity (MVPA) as well as 2-year change in MVPA. Pain outcomes included pain intensity (primary outcome) and analgesic use (secondary outcome)., Results: MVPA was inversely associated with pain intensity for adults with (odds ratio [OR], 0.84 [≥15 metabolic equivalent of task (MET) h/week vs. <7.5 MET h/week]; 95% confidence interval [CI], 0.76-0.93) and without (OR, 0.79; 95% CI, 0.75-0.82) a history of cancer. Compared to remaining inactive, participants who became sufficiently active (cancer: OR, 0.76; 95% CI, 0.68-0.86; no cancer: OR, 0.73; 95% CI, 0.69-0.77), became inactive (cancer: OR, 0.79; 95% CI, 0.71-0.88; no cancer: OR, 0.84; 95% CI, 0.80-0.89), or remained sufficiently active (cancer: OR, 0.66; 95% CI, 0.60-0.72; no cancer: OR, 0.62; 95% CI, 0.60-0.65) also reported less pain. Physical activity was not related to analgesic use., Conclusions: The relationship between physical activity and pain intensity was not substantially different between people with and without a history of cancer. Cancer survivors who perform more activity, or who increase their activity, may experience less pain than cancer survivors who consistently perform less., Plain Language Summary: People who have had cancer often experience ongoing pain. Being physically active may help reduce the intensity of the pain they experience., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC., Patients and Methods: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR., Results: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk., Conclusions: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions., (Copyright © 2024. Published by Elsevier Ltd.)

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., Competing Interests: Declaration of interests ESK is a co-investigator in a grant from National Institutes of Health (R01CA196569). JW is Stock shareholder of Gilead Sciences Inc. AK has received consulting fees for Illumina Inc., has participated on data safety monitoring boards or advisory boards of TensorBio, PatchBio, Serimmune, and OpenTargets, and has stock or stock options of Illumina, Freenome, Deep Genomics, Immunai, TensorBio, PatchBio, and Serimmune. MCS was a co-investigator in a grant from National Institutes of Health (R01CA201407). VM has received grant support from Instituto de Salud Carlos III and Fundacion Cientifica Asociación Española Contra el Cáncer. SBG is a co-founder of Brogent international LLC. JPL has received additional grant support (5P01CA196569, 6R01CA201407). The remaining authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways., Methods: This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders., Results: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05)., Conclusion: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer., (© 2024. The Author(s).)

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88., Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases)., Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066)., Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available., Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival., (©2024 American Association for Cancer Research.)

Background: Pre-diagnostic physical activity is reported to improve survival for women with breast cancer. However, studies of pre-diagnostic exposures and cancer survival are susceptible to bias, made clear when applying a target trial framework. We investigated the impact of selection bias, immortal time bias, confounding and bias due to inappropriate adjustment for post-exposure variables in a systematic review and meta-analysis of pre-diagnostic physical activity and survival after breast cancer., Methods: Medline, Embase and Emcare were searched from inception to November 2021 for studies examining pre-diagnostic physical activity and overall or breast cancer-specific survival for women with breast cancer. Random-effects meta-analysis was used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) comparing highest versus lowest pre-diagnostic physical activity. Subgroup meta-analyses were used to compare HRs of studies with and without different biases. ROBINS-E was used to assess risk of bias., Results: We included 22 studies. Women with highest versus lowest pre-diagnostic physical activity had higher overall and breast cancer-specific survival across most analyses. The overall risk of bias was high. We observed marked differences in estimated HRs between studies that did and did not adjust for post-exposure variables or have immortal time bias. All studies were at risk of selection bias due to participants becoming eligible for study when they have survived to post-exposure events (e.g., breast cancer diagnosis). Insufficient studies were available to investigate confounding., Conclusion: Biases can substantially change effect estimates. Due to misalignment of treatment assignment (before diagnosis), eligibility (survival to post-exposure events) and start of follow-up, bias is difficult to avoid. It is difficult to lend a causal interpretation to effect estimates from studies of pre-diagnostic physical activity and survival after cancer. Biased effect estimates that are difficult to interpret may be less useful for clinical or public health policy applications., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brigid Lynch reports financial support was provided by Victorian Cancer Agency. Frances Albers reports financial support was provided by Commonwealth of Australia. Ziyu Wang reports financial support was provided by China Scholarship Council. Brigid Lynch reports a relationship with SciLifeLab that includes: travel reimbursement., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer., Methods: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity., Results: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( P nonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; P het = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity., Conclusion: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Background: This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks + Escherichia coli (pks + E.coli + ), pks + E.coli - (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum)., Methods: We screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR., Results: Pks + E.coli + was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks + E.coli + and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks + E.coli - (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01)., Conclusion: Intratumoral pks + E.coli + but not pks + E.coli - are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause., (© 2024. The Author(s).)

Background: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations., Methods: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan., Results: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively., Conclusions: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer., Impact: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups., (©2023 American Association for Cancer Research.)

Objectives: It was previously estimated that 1814 (1.6 % of incident cancers) were attributable to physical inactivity in Australia in 2010, when only three sites were considered. We estimated the burden of cancer due to physical inactivity in Australia for 13 sites., Design: The population attributable fraction estimated site-specific cancer cases attributable to physical inactivity for 13 cancers. The potential impact fraction was used to estimate cancers that could have been prevented in 2015 if Australian adults had increased their physical activity by a modest amount in 2004-05., Methods: We used 2004-05 national physical activity prevalence data, 2015 national cancer incidence data, and contemporary relative-risk estimates for physical inactivity and cancer. We assumed a 10-year latency period., Results: An estimated 6361 of the cancers observed in 2015 were attributable to physical inactivity, representing 4.8 % of all cancers diagnosed. If Australian adults had increased their physical activity by one category in 2004-05, 2564 cases (1.9 % of all cancers) could have been prevented in 2015., Conclusions: More than three times as many cancers are attributable to physical inactivity than previously reported. Physical activity promotion should be a central component of cancer prevention programmes in Australia., Competing Interests: Declaration of interest statement None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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/m 2 ) increment in BMI levels was found to increase risks of Jass type 1 MSI-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 2 non-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 4 non-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 3 non-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., Competing Interests: Declaration of interests AB has received a Scholar-in-Training Award from AACR for 2023. VM has received grants from Instituto de Salud Carlos III and FC AECC. BML has received support from Uppsala University as a part of a presentation in the Svedberg Seminar Series, and she was the president of the Australasian Epidemiological Association (2020–2023). BVG has received support grant from World Cancer Research Fund for a separate project within the same research field. AET has received an editorial board fee from NIH PDQ Cancer Genetics. MG has received research funding from Janssen and Servier, consulting fees from Nerviano Medical Sciences, Chromacode, and AstraZeneca and support to attend a meeting from Dava Oncology. JN has received research funding from Natera Inc and consulting fees from Leica Biosciences. MAJ has received an NIH funding. The remaining authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Pancreatic cancer is currently the seventh leading cause of cancer death worldwide. Understanding whether modifiable factors increase or decrease the risk of this disease is central to facilitating primary prevention. Several epidemiological studies have described the benefits of physical activity, and the risks associated with sedentary behavior, in relation to cancer. This study aimed to assess evidence of causal effects of physical activity and sedentary behavior on pancreatic cancer risk. We conducted a two-sample Mendelian randomization study using publicly available data for genetic variants associated with physical activity and sedentary behavior traits and genetic data from the Pancreatic Cancer Cohort Consortium (PanScan), the Pancreatic Cancer Case-Control Consortium (PanC4), and the FinnGen study for a total of 10 018 pancreatic cancer cases and 266 638 controls. We also investigated the role of body mass index (BMI) as a possible mediator between physical activity and sedentary traits and risk of developing pancreatic cancer. We found evidence of a causal association between genetically determined hours spent watching television (hours per day) and increased risk of pancreatic cancer for each hour increment (PanScan-PanC4 odds ratio = 1.52, 95% confidence interval 1.17-1.98, P = .002). Additionally, mediation analysis showed that genetically determined television-watching time was strongly associated with BMI, and the estimated proportion of the effect of television-watching time on pancreatic cancer risk mediated by BMI was 54%. This study reports the first Mendelian randomization-based evidence of a causal association between a measure of sedentary behavior (television-watching time) and risk of pancreatic cancer and that this is strongly mediated by BMI. Summary: Pancreatic cancer is a deadly disease that is predicted to become the second leading cause of cancer-related deaths by 2030. Physical activity and sedentary behaviors have been linked to cancer risk and survival. However, there is limited research on their correlation with pancreatic cancer. To investigate this, we used a Mendelian randomization approach to examine the genetic predisposition to physical activity and sedentariness and their relation to pancreatic cancer risk, while excluding external confounders. Our findings revealed a causal link between the time spent watching television and an increased risk of pancreatic cancer. Additionally, we determined that over half of the effect of watching television on pancreatic risk is mediated by the individual's BMI., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Cardiovascular disease (CVD) is the leading cause of mortality and disability globally. We examined healthcare service utilization and costs attributable to CVD in Ireland in the period before the introduction of a major healthcare reform in 2016., Methods: Secondary analysis of data from 8 113 participants of the first wave of The Irish Longitudinal Study on Ageing. CVD was defined as having a self-reported doctor's diagnosis of myocardial infarction, angina, heart failure, stroke, atrial fibrillation or transient ischaemic attack. Participants self-reported the utilization of healthcare services in the year preceding the interview. Negative binomial regression with average marginal effects (AME) was used to estimate the incremental number of general practitioner (GP) and outpatient department (OPD) visits, accident and emergency department attendances and hospitalisations in population with CVD relative to population without CVD. We calculated the corresponding costs at individual and population levels, by gender and age groups., Results: The prevalence of CVD was 18.2% (95% CI: 17.3, 19.0) Participants with CVD reported higher utilization of all healthcare services. In adjusted models, having CVD was associated with incremental 1.19 (95% CI: 0.99, 1.39) GP and 0.79 (95% CI: 0.65, 0.93) OPD visits. There were twice as many incremental hospitalisations in males with CVD compared to females with CVD (AME (95% CI): 0.20 (0.16, 0.23) vs 0.10 (0.07, 0.14)). The incremental cost of healthcare service use in population with CVD was an estimated €352.2 million (95% CI: €272.8, €431.7), 93% of which was due to use of secondary care services., Conclusion: We identified substantially increased use of healthcare services attributable to CVD in Ireland. Continued efforts aimed at CVD primary prevention and management are required., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Physical activity can provide analgesic benefit but its effect on cancer-related pain is unclear. This review synthesised and appraised the evidence for the effect of physical activity on pain in people living with or beyond cancer., Methods: A systematic search of Ovid Medline and Embase was performed to identify randomised controlled trials (RCTs), randomised cross-over studies (RXTs), and prospective observational studies that examined physical activity and pain outcomes in adults living with or beyond cancer. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to assess evidence quality., Results: One hundred twenty-one studies (n = 13,806), including 102 RCTs, 6 RXTs, and 13 observational studies, met the criteria for inclusion. Meta-analyses of RCTs identified a decrease in pain intensity (n = 3734; standardised mean difference (SMD) - 0.30; 95% confidence interval (CI) - 0.45, - 0.15) and bodily pain (n = 1170; SMD 0.28; 95% CI 0.01, 0.56) but not pain interference (n = 207; SMD - 0.13, 95% CI - 0.42, 0.15) following physical activity interventions. Individual studies also identified a reduction in pain sensitivity but not analgesic use, although meta-analysis was not possible for these outcomes. High heterogeneity between studies, low certainty in some effect estimates, and possible publication bias meant that evidence quality was graded as very low to low., Conclusion: Physical activity may decrease pain in people living with and beyond cancer; however, high heterogeneity limits the ability to generalise this finding to all people with cancer or to specific types of cancer-related pain., (© 2024. The Author(s).)

Background: We examined associations between adherence to adaptations of the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and total, exposure-related and site-specific cancer risk., Methods: A total of 20,001 participants ages 40 to 69 years at enrollment into the Melbourne Collaborative Cohort Study in 1990 to 1994, who had diet, body size, and lifestyle reassessed in 2003 to 2007 ("baseline"), were followed-up through June 2021. We constructed diet and standardized lifestyle scores based on core WCRF/AICR recommendations on diet, alcohol intake, body size and physical activity, and additional scores incorporating weight change, sedentary behavior, and smoking. Associations with cancer risk were estimated using Cox regression, adjusting for confounders., Results: During follow-up (mean = 16 years), 4,710 incident cancers were diagnosed. For highest quintile ("most adherent") of the standardized lifestyle score, compared with lowest ("least adherent"), a HR of 0.82 [95% confidence interval (CI): 0.74-0.92] was observed for total cancer. This association was stronger with smoking included in the score (HR = 0.74; 95% CI: 0.67-0.81). A higher score was associated with lower breast and prostate cancer risk for the standardized score, and with lung, stomach, rectal, and pancreatic cancer risk when the score included smoking. Our analyses identified alcohol use, waist circumference and smoking as key drivers of associations with total cancer risk., Conclusions: Adherence to WCRF/AICR cancer prevention recommendations is associated with lower cancer risk., Impact: With <0.2% of our sample fully adherent to the recommendations, the study emphasizes the vast potential for preventing cancer through modulation of lifestyle habits., (©2023 American Association for Cancer Research.)

No randomized controlled trial has evaluated the effect of long-term alcohol interventions on mortality. Results reported in existing observational studies may be subject to selection bias and time-varying confounding. Using data from the Australian Longitudinal Study on Women's Health 1946-1951 birth cohort, collected regularly from 1996-2016, we estimated all-cause and cancer mortality had women been assigned various alcohol interventions (in categories ranging from 0 to >30 g/day ethanol, or reduced to ≤20 g/day if higher) at baseline, and had they maintained these levels of consumption. The cumulative risks for all-cause and cancer mortality were 5.6% (10,118 women followed for 20 years) and 2.9% (18 years), respectively. For all-cause and cancer mortality, baseline ethanol up to 30 g/day showed lower risk and >30 g/day showed higher risk relative to abstention. Had women sustainedly followed the interventions, a similar relationship was observed for all-cause mortality. However, the negative association observed for intakes ≤30 g/day and positive association for intakes >30 g/day was not evident for cancer mortality. Our findings suggest that all-cause mortality could have been lower than observed if this cohort of women had consumed some alcohol (no more than 30 g/day) rather than no consumption, but cancer mortality might not., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Sedentary behaviours have been associated with increased risks of some common cancers in epidemiological studies; however, it is unclear if these associations are causal., Methods: We used univariable and multivariable two-sample Mendelian randomisation (MR) to examine potential causal relationships between sedentary behaviours and risks of breast, colorectal and prostate cancer. Genetic variants associated with self-reported leisure television watching and computer use were identified from a recent genome-wide association study (GWAS). Data related to cancer risk were obtained from cancer GWAS consortia. A series of sensitivity analyses were applied to examine the robustness of the results to the presence of confounding., Results: A 1-standard deviation (SD: 1.5 h/day) increment in hours of television watching increased risk of breast cancer (OR per 1-SD: 1.15, 95% confidence interval [CI]: 1.05-1.26) and colorectal cancer (OR per 1-SD: 1.32, 95% CI: 1.16-1.49) while there was little evidence of an association for prostate cancer risk (OR per 1-SD: 0.94, 95% CI: 0.84-1.06). After adjusting for years of education, the effect estimates for television watching were attenuated (breast cancer, OR per 1-SD: 1.08, 95% CI: 0.92-1.27; colorectal cancer, OR per 1-SD: 1.08, 95% CI: 0.90-1.31). Post hoc analyses showed that years of education might have a possible confounding and mediating role in the association between television watching with breast and colorectal cancer. Consistent results were observed for each cancer site according to sex (colorectal cancer), anatomical subsites and cancer subtypes. There was little evidence of associations between genetically predicted computer use and cancer risk., Conclusions: Our univariable analysis identified some positive associations between hours of television watching and risks of breast and colorectal cancer. However, further adjustment for additional lifestyle factors especially years of education attenuated these results. Future studies using objective measures of exposure can provide new insights into the possible role of sedentary behaviour in cancer development., (© 2023 World Health Organization; licensed by John Wiley & Sons Ltd. Cancer Medicine published by John Wiley & Sons Ltd.)