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Importance: The proportion of colorectal cancer (CRC) cases attributable to excess weight, known as population attributable fraction (PAF), has been commonly based on measures of body mass index (BMI). Central obesity metrics, such as waist circumference (WC) and waist to hip ratio (WHR), are potentially better indicators of adiposity and have demonstrated stronger associations with CRC incidence., Objectives: To examine PAFs of CRC cases that are attributable to high WC and WHR and compare them to those attributable to high BMI., Design, Setting, and Participants: This population-based UK Biobank cohort study included 458 543 individuals aged 40 to 69 years at recruitment (March 2006 to July 2010) living within a reasonable distance of the 22 assessment centers across the UK. The analyses were conducted between May and July 2024., Exposures: Exposures were BMI, as a measure of general obesity, and WC and WHR, as indicators of central obesity., Main Outcomes and Measures: Hazard ratios (HRs) and corresponding 95% CIs were calculated for the associations of BMI, WC, and WHR with CRC incidence. The PAFs and 95% CIs of CRC cases attributable to high BMI, WC, and WHR were also calculated., Results: A total of 458 543 participants (median [IQR] age, 57 [50-63] years; 244 351 [53.3%] female) were included in the study. During a median follow-up of 11.8 (IQR, 10.9-12.5) years, 5944 participants were diagnosed with CRC. The HRs for the association with CRC incidence were notably smaller for BMI (HR for the highest vs lowest BMI quartile, 1.23; 95% CI, 1.14-1.33) than for WC (HR for the highest vs lowest WC quartile, 1.37; 95% CI, 1.27-1.49) and WHR (HR for the highest vs lowest WHR quartile, 1.40; 95% CI, 1.29-1.51); these associations became comparable only after accounting for possible reverse causality by excluding the initial years of follow-up. Similarly, the PAF of CRC for high BMI was 9.9% (95% CI, 5.5%-14.4%), substantially lower than the PAFs for high WC and WHR, which were 17.3% (95% CI, 12.3%-22.1%) and 17.6% (95% CI, 12.9%-22.2%), respectively. After excluding the initial 7 years of follow-up, PAF estimates became analogous across all measures of obesity and were 15.7% (95% CI, 8.9%-22.4%) for BMI, 16.9% (95% CI, 9.8%-23.8%) for WC, and 18.0% (95% CI, 11.5%-24.6%) for WHR., Conclusions and Relevance: In this cohort study of approximately half a million participants, the PAF of CRC attributable to excess weight, defined as high BMI, was considerably underestimated. The PAFs attributable to WC and WHR were consistent and much higher, underlining the importance of efforts to limit and overcome the obesity epidemic in CRC prevention.

Objective: To evaluate the magnitude of the potential underestimation of the proportion of cancer cases attributable to excess weight, known as population attributable fraction (PAF), due to potential bias from prediagnostic weight loss already present at baseline of cohort studies and to overcome it as much as possible., Methods: Data from the UK Biobank cohort participants aged 40-69 without prior cancer diagnosis were analyzed. We assessed the magnitude of associations of excess weight with the incidence of obesity-related cancers combined, and separately for gastrointestinal (GI) and other cancers. Using multivariable Cox proportional hazards models, hazard ratios (HR) and their 95% confidence intervals (CI), and PAFs for excess weight at baseline were estimated for various periods of time after weight measurements., Findings: Of 458,660 participants, 20,218 individuals developed obesity-related cancers during a median 11.0-year follow-up, comprising 8,460 GI, and 11,765 non-GI cancers. PAFs were much higher for cancers occurring more than four years after recruitment than for cancers occurring within the initial four years: 17.7% versus 7.2%, 21.4% versus 11.7% for GI, non-GI and all obesity-related cancers combined, respectively. With respect to total cancer (including cancers with no established relationship with excess weight), PAFs were estimated as 5.1% and 8.8% for the 0-4 and 4-14-year periods of follow-up., Conclusion: The proportion of cancers attributable to excess weight is likely substantially larger than previously estimated based on cohort studies with short follow-up time or no or only limited exclusion of the early years of follow-up from the analyses., (© 2024. The Author(s).)

Background: Post-surgery blood-based biomarkers may be useful for guiding treatment and surveillance decisions among colorectal cancer (CRC) patients. However, most candidate biomarkers provide little if any predictive value beyond stage at diagnosis. We aimed to investigate the independent prognostic value of post-operative serum C-reactive protein (CRP), a highly sensitive biomarker of inflammation, for long-term CRC outcomes in two large patient cohorts., Materials and Methods: CRP levels were measured from serum samples of CRC patients collected ≥1 month post-surgery in the German DACHS (n = 1416) and the UK Biobank (n = 1149) cohorts. Associations of post-operative CRP with overall survival (OS) and CRC-specific survival (CSS) were assessed using Cox regression and presented as hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for key sociodemographic and clinical covariates., Results: In both cohorts, consistent strong dose-response relationships between post-operative CRP and both OS and CSS were observed. Adjusted HRs (95% CI) for CRP >10 versus <3 mg/l were 1.93 (1.58-2.35) and 2.70 (2.03-3.59) in the DACHS cohort, and 2.70 (1.96-3.71) and 2.61 (1.83-3.72) in the UK Biobank cohort, respectively. Associations between post-operative CRP and OS were particularly strong among younger patients (<65 years at diagnosis; P value for interaction by age <0.01)., Conclusions: Serum CRP determined a month or more after surgery may be useful as a strong independent prognostic biomarker for guiding therapeutic decisions and for surveillance of the course of disease of CRC patients, particularly those <65 years of age at diagnosis., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The association between excess weight and colorectal cancer (CRC) risk may have been underestimated due to potential weight loss during pre-clinical sojourn time of CRC. We aimed to investigate this association and the corresponding population attributable fraction (PAF), accounting for prediagnostic weight loss., Methods: Data from the UK Biobank prospective cohort were used. Multivariable adjusted hazard ratios (HR) and their 95% confidence intervals (CI) for various periods of follow-up and the corresponding PAF of excess weight were calculated., Results: During a median of 10.0 years of follow-up, of 453,049 participants, 4794 developed CRC. The excess weight-CRC association became substantially stronger with including increasing lengths of follow-up in the analyses and further excluding the initial years of follow-up. HRs (95% CIs) for overweight and obesity were 1.06 (0.97-1.16) and 1.14 (1.03-1.26) after 7 years of follow-up, 1.13 (1.05-1.21) and 1.23 (1.14-1.33) when including complete follow-up length, and 1.26 (1.12-1.43) and 1.42 (1.24-1.63) when excluding the initial 7 years of follow-up. The corresponding PAFs of excess weight were estimated as 6.8%, 11.3%, and 19.0%, respectively., Conclusions: Comprehensive consideration of the potential effect of prediagnostic weight loss discloses a much stronger impact of excess body weight on CRC risk than previously assumed., (© 2023. The Author(s).)

Artificial intelligence (AI) can predict the presence of molecular alterations directly from routine histopathology slides. However, training robust AI systems requires large datasets for which data collection faces practical, ethical and legal obstacles. These obstacles could be overcome with swarm learning (SL), in which partners jointly train AI models while avoiding data transfer and monopolistic data governance. Here, we demonstrate the successful use of SL in large, multicentric datasets of gigapixel histopathology images from over 5,000 patients. We show that AI models trained using SL can predict BRAF mutational status and microsatellite instability directly from hematoxylin and eosin (H&E)-stained pathology slides of colorectal cancer. We trained AI models on three patient cohorts from Northern Ireland, Germany and the United States, and validated the prediction performance in two independent datasets from the United Kingdom. Our data show that SL-trained AI models outperform most locally trained models, and perform on par with models that are trained on the merged datasets. In addition, we show that SL-based AI models are data efficient. In the future, SL can be used to train distributed AI models for any histopathology image analysis task, eliminating the need for data transfer., (© 2022. The Author(s).)

Background: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR)., Methods: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (OR SD ) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions., Results: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (OR SD  = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown., Conclusions: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.

Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development., Methods: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10 -4 ). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10 -5 ). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2., Conclusions: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)