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 BMI, tumor microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) 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 ratio (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: 1.15-1.22). 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 MSI-H, CIMP-low/negative, BRAF-wildtype, KRAS-wildtype, OR, 1.04, 95%CI: 0.90-1.20). 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.
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.
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