INTRODUCTION: Incidence of colorectal cancer (CRC) in young adults has been increasing in recent decades in many countries for still widely unclear reasons. Suspected candidates include increasing prevalence of overweight and obesity, but specific evidence on their role for early-onset CRC (EOCRC) is sparse. We conducted a systematic review and meta-analysis to summarize available evidence on the association of body mass index (BMI) with EOCRC. METHODS: We systematically searched PubMed, EMBASE, and Web of Science up to February 2021 for studies that evaluated the association of BMI (before diagnosis but not near diagnosis) with CRC risk and reported specific results for EOCRC. Results from studies with similar BMI groupings were summarized in meta-analyses using random-effects models. RESULTS: Twelve studies were eligible and included. Results of 6 studies were pooled in meta-analyses, which yielded a higher risk of EOCRC for overweight and obesity (BMI ≥25 kg/m²) compared with normal weight (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.19–1.68). An increasing risk with increasing BMI was observed, with much higher risk for obesity (OR 1.88, 95% CI 1.40–2.54) than for overweight (OR 1.32, 95% CI 1.19–1.47). DISCUSSION: Obesity is a strong risk factor for EOCRC, and its increasing prevalence in younger generations is likely to substantially contribute to the increase in EOCRC. Efforts to limit the obesity epidemic in adolescents and younger adults may be crucial for reducing CRC incidence in future generations of adults.

Evidence is lacking on the impact of alcohol consumption on colorectal cancer (CRC) risk (overall and by age at diagnosis) by polygenic risk score (PRS) levels, and it is unclear how the magnitude of CRC risk associated with alcohol consumption compares to the magnitude of genetically determined risk. Multiple logistic regression was used to assess the association between alcohol consumption and colorectal cancer (CRC) across PRS levels based on 140 CRC-related loci among 5104 CRC cases and 4131 controls from a large population-based case-control study. We compared the effects for alcohol consumption and PRS on CRC risk using the “Genetic Risk Equivalent (GRE)” for effective risk communication. Specific analyses were conducted for early-onset CRC (EOCRC, <55 years) and late-onset CRC (LOCRC, ≥55 years). High alcohol consumption, and to a lower extent, also alcohol abstinence were associated with increased CRC risk. Compared to low alcohol consumption (0·1-<25 g/d), lifetime average alcohol consumption ≥25 g/d was more strongly associated with EOCRC [odds ratio (OR) 1·8, 95% confidence interval (CI) 1·2–2·8] than with LOCRC risk (OR 1·3, 95% CI 1·1–1·4) (P-value for interaction with age =0·011). Interactions between alcohol consumption and PRS did not reach statistical significance for either EOCRC or LOCRC risk. The estimated impact of high lifetime alcohol consumption on EOCRC was equivalent to the effect of having 47 percentiles higher PRS (GRE 47, 95% CI 12–82), stronger than the impact on LOCRC (GRE 18, 95% CI 8–29). Excessive alcohol use was strongly associated with EOCRC risk, independent of PRS levels. Abstaining from heavy drinking could reduce risk for CRC, in particular for EOCRC to an extent that would be equivalent to having a much lower genetically determined risk. The first author (X.C.) was supported by the Guangzhou Elite Project (GEP). The DACHS study was supported by grants from the German Research Council (BR 1704/6–1, BR1704/6–3, BR 1704/6–4, BR 1704/6–6, CH 117/1–1, BR 1704/17–1, HO 5117/2–1) and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01GL1712).

Incidence of colorectal cancer (CRC) in younger adults is increasing in many countries. Smoking is an established risk factor of CRC risk, but evidence on its impact on early-onset CRC (EOCRC) risk is limited. We aimed to evaluate the association of smoking exposure with EOCRC and compare it with late-onset CRC (LOCRC). Smoking history and other known or suspected CRC risk factors were ascertained in detail in personal interviews among 6264 CRC patients and 6866 controls (frequency matched for age, sex, and county of residence) who were recruited in 2003-2020 in the DACHS study (Darmkrebs: Chancen der Verhütung durch Screening [German]; Colorectal Cancer: Chances for Prevention Through Screening [English]), a population-based case-control study from Germany. Associations of smoking with EOCRC (<55 years, 724 cases, 787 controls) and LOCRC (≥55years, 5540 cases, 6079 controls) were estimated using multiple logistic regression. Smoking exposure was much higher among EOCRC cases than among controls, and strong associations of smoking were observed for both EOCRC and LOCR. Adjusted odds ratios for EOCRC and LOCRC were as follows: current smoking: 1.57 (95% confidence interval [CI] = 1.20 to 2.04, P < .001) and 1.46 (95% CI = 1.28 to 1.67, P < .001); former smoking: 1.39 (95% CI = 1.07 to 1.81, P = .01) and 1.24 (95% CI = 1.13 to 1.36, P < .001); per 10 pack-years: 1.15 (95% CI = 1.05 to 1.27, P < .001) and 1.05 (95% CI = 1.03 to 1.08, P < .001). These patterns were similar for colon and rectum cancer and for early- and late-stage CRC. Smoking is a strong risk factor for both EOCRC and LOCRC.

Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. 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. 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). 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.

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Summary: Background: The regular use of non‐steroidal anti‐inflammatory drugs (NSAIDs) has been associated with reduced colorectal cancer (CRC) risk.Aim: To explore whether this association varies according to background polygenic risk for CRC.Methods: Data were collected from a large population‐based case‐control study on CRC in Germany. A polygenic risk score (PRS) based on 140 CRC‐related risk loci was used to quantify the genetic risk. The associations of regular use of NSAIDs (≥2times per week for at least 1 year) with CRC risk were estimated in the whole population and in subgroups according to PRS levels using multivariable logistic regression. The impact of NSAIDs on CRC risk was compared to PRS using the ‘genetic risk equivalent’ (GRE), a recently developed metric for effective risk communication.Results: In total 5129 CRC cases and 4093 controls were included in this analysis. The regular use of NSAIDs (including aspirin) was associated with reduced CRC risk [odds ratio (OR) 0.66, 95% confidence interval (CI) 0.59, 0.74], as was regular use of aspirin only (OR 0.73, 95% CI 0.65, 0.83), without indication of interaction with the PRS (P = 0.10 and 0.22 respectively). The effect of NSAID use was equivalent to the effect of having a 32 percentiles lower PRS (GRE −32, 95% CI −41, −22).Conclusions: The regular use of NSAIDs is associated with greatly reduced CRC risk regardless of individual genetic profile. With an equivalent reduction of relative risk across all polygenic risk groups, absolute risk reduction would be expected to be strongest among those with the highest polygenic risk score.