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.

The underestimated impact of excess body weight on colorectal cancer risk: Evidence from the UK Biobank cohort.

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.

Association of Overweight, Obesity, and Recent Weight Loss With Colorectal Cancer Risk.

Importance: Overweight and obesity, conditions with rising prevalence in many countries, are associated with increased colorectal cancer (CRC) risk. However, many patients with CRC lose weight before diagnosis, which may lead the association to be underestimated. Objective: To evaluate the association of body mass index (BMI) and weight change with CRC risk when considering BMI at different time frames, with the intention to account for prediagnostic weight loss. Design, Setting, and Participants: This population-based case-control study was conducted in southwestern Germany between 2003 and 2021. Cases with a first diagnosis of CRC and controls (frequency matched by age, sex, and county) with comprehensive risk factor information and self-reported weight at different time points were included. Data were analyzed between October 2022 and March 2023. Exposure: BMI and weight change at different time frames before the time of diagnosis (cases) or recruitment (controls). Main Outcomes and Measures: Association of BMI and weight change at various points in time before and up to diagnosis with CRC, assessed by multivariable logistic regression with comprehensive confounder adjustment. Results: A total of 11 887 participants (6434 CRC cases, 5453 controls; median [IQR] age, 69 [61-77] years; 7173 male [60.3%]) were included. At the time of diagnosis, 3998 cases (62.1%) and 3601 controls (66.0%) were overweight or obese, suggesting an inverse association between excess weight and CRC risk. Conversely, we found significant positive associations of overweight (adjusted odds ratio [aOR], 1.27; 95% CI, 1.03-1.56), obesity (aOR, 2.09; 95% CI, 1.61-2.70), and a 5-unit increase in BMI (aOR, 1.35; 95% CI, 1.21-1.50) with CRC risk when using BMI measured 8 to 10 years before diagnosis. High BMI as a risk factor for CRC was increased as earlier periods before diagnosis were examined, with the association being particularly pronounced using BMI at least 8 years before diagnosis. An opposite trend was found for the association of weight loss (at or exceeding 2 kg) with CRC, with the greatest effect sizes occurring for weight loss within 2 years before diagnosis (aOR, 7.52; 95% CI, 5.61-10.09), and gradually decreased for earlier intervals. Conclusions and Relevance: In this population-based case-control study, accounting for substantial prediagnostic weight loss further highlighted the association of overweight and obesity with CRC risk.

Is the association of overweight and obesity with colorectal cancer underestimated? An umbrella review of systematic reviews and meta-analyses.

Although high body-mass index (BMI) is associated with increased risk of developing colorectal cancer (CRC), many CRC patients lose weight before diagnosis. BMI is often reported close to diagnosis, which may have led to underestimation or even reversal of direction of the BMI-CRC association. We aimed to assess if and to what extent potential bias from prediagnostic weight loss has been considered in available epidemiological evidence. We searched PubMed and Web of Science until May 2022 for systematic reviews and meta-analyses investigating the BMI-CRC association. Information on design aspects and results was extracted, including if and how the reviews handled prediagnostic weight loss as a potential source of bias. Additionally, we analyzed how individual cohort studies included in the latest systematic review handled the issue. Overall, 18 reviews were identified. None of them thoroughly considered or discussed prediagnostic weight loss as a potential source of bias. The majority (15/21) of cohorts included in the latest review did not exclude any initial years of follow-up from their main analysis. Although the majority of studies reported having conducted sensitivity analyses in which initial years of follow-up were excluded, results were reported very heterogeneously and mostly for additional exclusions of 1-2 years only. Where explicitly reported, effect estimates mostly increased with increasing length of exclusion. The impact of overweight and obesity on CRC risk may be larger than suggested by the existing epidemiological evidence.

Body mass index and molecular subtypes of colorectal cancer.

BACKGROUND: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. METHODS: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. RESULTS: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control). CONCLUSIONS: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.

Assessment of Body Mass Index, Polygenic Risk Score, and Development of Colorectal Cancer.

Importance: Excess weight, the prevalence of which is high and increasing in many countries, is linked to multiple adverse health outcomes, including increased colorectal cancer (CRC) risk. Better communication of health risks associated with excess weight might support efforts of prevention. Objective: To evaluate the individual and joint associations of body mass index (BMI) and polygenic risk with CRC, to assess potential interactions among them, and to quantify by how much increased polygenic risk for CRC can be offset by having a BMI within reference range. Design, Setting, and Participants: This population-based case-control study was conducted in the Rhine-Neckar region of southwest Germany, with recruitment from 2003 to 2017. Participants with both risk factor and genetic information were included for analysis. Data analysis was conducted from December 8, 2021, to February 17, 2022. Exposures: BMI was calculated as self-reported weight in kilograms approximately 10 years before diagnosis or interview and current height in meters squared. A polygenic risk score (PRS) was built based on 140 CRC-related risk loci. Main Outcomes and Measures: Individual and joint associations of BMI and PRS with CRC were estimated using multiple logistic regression. Associations of excess weight with CRC were quantified by adjusted odds ratios (aORs) and genetic risk equivalents (GREs), the equivalent outcomes conveyed by defined differences in PRS percentiles. Results: Among 9169 participants (median [IQR] age, 69 [62-76] years; 5589 [61.0%] male participants) included, 5053 had CRC and 4116 did not. BMI of 30 or greater was associated with higher odds of having CRC compared with BMI less than 25 (aOR, 1.71; 95% CI, 1.49-1.97), independent of PRS levels (P for interaction = .45). Participants with BMI of 30 or greater and a PRS in the highest tertile had higher odds of CRC compared with participants with BMI less than 25 and a PRS in the lowest tertile (aOR, 3.82; 95% CI, 3.03-4.82). The estimated association of BMI greater than 30 with CRC risk was equivalent to that of having a 41 (95% CI, 29-53)-percentile higher PRS. BMI of 30 or greater was particularly associated with stage IV CRC (aOR, 2.21; 95% CI, 1.71-2.84). Conclusions and Relevance: These findings suggest that excess weight was associated with CRC regardless of PRS levels. The association of having a BMI within reference range may be similar to that of having a substantially lower polygenic risk for CRC.