Yujia Lu

Background: Current sedentary behavior (SB) guidelines primarily emphasize total time spent sedentary. We explored differences between interrupted and prolonged SB in relation to a range of cancer outcomes. Methods and findings: This study included 91,292 UK Biobank participants with valid accelerometer data. Participants were followed for a median of 12.38 years (interquartile range 11.56–13.15 years). A two-step approach based on a random forest model was used to classify SB. Multivariable Cox proportional hazards models were applied to overall incident cancers and cancer deaths, plus obesity-related and type-2 diabetes-related cancers, and 23 site-specific cancers. Models were adjusted for demographic, socioeconomic, lifestyle, dietary, and health-status factors, including age, ethnicity, deprivation, education, smoking, alcohol intake, diet, and morbidity count. Isotemporal substitution models were used to estimate the associated cancer risk when replacing prolonged SB with intermittent SB, or physical activity (PA). After adjusting for sociodemographic and lifestyle factors, each additional hour of prolonged SB was associated with a higher risk of overall cancer mortality (hazard ratio [HR] HR _1hour 1.09; 95% confidence interval [CI] [1.06, 1.11]; p < 0.001). Replacing 1 hour per day of prolonged SB with light PA (HR _LPA 0.88; 95% CI [0.79, 0.99]; p = 0.033) was associated with lower risk of overall cancer mortality. Similarly, replacing 30 min per day of prolonged SB with moderate PA (HR _MPA 0.92; 95% CI [0.86, 0.99]; p = 0.024) was associated with a lower risk of overall cancer mortality. The main methodological limitations were observational design, residual confounding, healthy volunteer bias, and measurement imprecision due to having only 7 days of accelerometer wear. Conclusion: Cancer risk associated with SB is specific to prolonged SB. Replacing prolonged SB physical activity is associated with lower cancer risk.

Background: High ultra-processed food (UPF) intake has been linked to colorectal cancer (CRC), but underlying mechanisms remain unclear. Objective: To evaluate a metabolomic pattern of UPF intake and its association with CRC risk. Design: Integrating food frequency questionnaire data and high-throughput metabolomic profiling in 1740 participants (mean age at blood draw: 59.9 years; >95% non-Hispanic white participants) from nested case-control studies within the Nurses’ Health Study and Health Professionals Follow-up Study, we derived and validated a UPF-related metabolomic pattern as a weighted sum of metabolites selected via elastic net regression with 10-fold cross-validation. We evaluated prospective associations of this pattern and individual metabolites with CRC risk using multivariable conditional logistic regression in 686 pairs of incident CRC cases and matched controls. Results: Among 222 metabolites, we constructed a UPF metabolomic pattern comprising 50 metabolites, primarily lipids and amino acids, with 22 positively and 28 inversely associated with total UPF intake (pattern vs intake: Spearman rho=0.35). The pattern was associated with higher CRC risk (highest vs lowest quintile: OR (95% CI) 1.71 (1.15 to 2.53), p value trend=0.002). Correlations of individual metabolites with UPF intake were moderately aligned with their associations with CRC risk (rho=0.50). N2, N2-dimethylguanosine, a marker of meat/poultry intake, was positively associated with CRC risk (1.96 (1.27 to 3.03)), while 21-deoxycortisol, related to cortisol biosynthesis, was inversely associated (0.59 (0.41 to 0.86)). Conclusion: We developed a UPF metabolomic pattern. The pattern and several metabolites were associated with CRC risk, providing biological insights into potential pathways underlying the UPF-CRC relationship.

Table S3 shows the interaction between hormone levels and adiposity on cancer incidence excluding individuals with less than one and 5 years of follow-up

The role of sex hormones in the sex difference between adiposity and cancer risk remains unclear. We examined body mass index (BMI) and visceral adipose tissue (VAT) estimated using a validated equation in relation to cancer incidence according to serum sex hormone–binding globulin (SHBG), testosterone, and estradiol among 451,500 UK Biobank participants. For cancers showing a sex-specific adiposity association, we used Cox regression to calculate multivariable HRs per increase between the 10th and 90th percentiles of adiposity according to low versus high sex hormone levels. We documented 42,949 cancers over a median follow-up of 13.1 years. BMI and VAT were more strongly associated with a higher risk of esophageal, liver, and colorectal cancers in males than in females. In males, BMI showed a stronger association with esophageal (HR for high vs. low SHBG = 2.38 vs. 1.62; Pinteraction = 0.04) and liver cancers (HR = 3.24 vs. 1.96; Pinteraction = 0.03) among those with high versus low SHBG, whereas an opposite pattern was observed for colorectal cancer (HR = 1.12 vs. 1.47; Pinteraction = 0.03). Among females, BMI was associated with a higher esophageal cancer risk in those with low (HR = 1.68) but not high SHBG (HR = 0.64; Pinteraction = 0.025); for liver cancer, results were similar but statistically nonsignificant. No interaction by estradiol or testosterone was detected. Similar results were observed for VAT. SHBG may be an important factor underlying the sex difference in adiposity-associated risk for colorectal, esophageal, and liver cancers.Prevention Relevance:Understanding the interactions between sex hormones and adiposity can help explain sex differences in cancer risk associated with body fat. Our findings suggest that SHBG may be a promising target for future research on strategies to reduce the risk of colorectal, esophageal, and liver cancers in individuals with excess adiposity.

Table S2 shows the interaction between hormone levels and adiposity on cancer incidence among never smokers

Figure S1 shows the exclusions made to the UK Biobank study population to form our analytic population

Figure S2 shows the distribution of estradiol, testosterone, and SHBG by sex and the median values used as cut points

Table S1 shows the interaction between hormone levels and adiposity on cancer incidence among post-menopausal females

Background:Mechanistic data indicate the benefit of short-chain fatty acids (SCFA) produced by gut microbial fermentation of fiber on colorectal cancer, but direct epidemiologic evidence is limited. A recent study identified SNPs for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits.Methods:We conducted a two-sample Mendelian randomization analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to colorectal cancer risk in three large European genetic consortia of 58,131 colorectal cancer cases and 67,347 controls. We estimated the risk of overall colorectal cancer and conducted subgroup analyses by sex, age, and anatomic subsites of colorectal cancer.Results:We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall colorectal cancer, colorectal cancer by sex, or early-onset colorectal cancer (diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD, 0.95; 95% confidence intervals, 0.91–0.99; P = 0.03) but it did not surpass multiple testing of subgroup analysis.Conclusions:Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with colorectal cancer risk.Impact:Fecal propionate and PWY-5022 may not have a substantial influence on colorectal cancer risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on colorectal cancer risk.

Supplementary Table 1 shows the power calculation for the associations of PWY-5022 and propionate with CRC risk.