Higher body mass index (BMI) is associated with increased risk of colorectal cancer, more so for men than for women, according to study results published in the Journal of the National Cancer Institute. Additionally, a certain variant of the gene SMAD7 and BMI may jointly influence colorectal cancer risk in women.

Colorectal cancer has a complex etiology in which missing heritability can be explained by gene-by-environment (GxE) interactions. BMI is an established risk factor for colorectal cancer. However, the underlying pathophysiology of the BMI-colorectal cancer association is not fully understood. To date, no consistent GxE interactions have been identified from candidate gene or genome-wide association studies (GWAS).

In the study, researchers tested for multiplicative statistical interactions between approximately 2.7 million single nucleotide polymorphisms (SNPs) and BMI (per 5 kg·m2) with risk of colorectal adenocarcinoma. Analysis was based on 14,059 colorectal cancer cases (53.2% women) and 14,416 control cases (53.8% women) from GWA studies included in the multi-centered Colon-Cancer Family Registry, the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), and the ColoRectal Transdisciplinary Study. Diagnoses of colorectal adenocarcinoma were confirmed by abstraction of medical records, pathology reports, cancer registry linkage, or death certificates, while controls were confirmed by a negative colonoscopy or a negative sigmoidoscopy. All analyses were stratified by sex a priori. Statistical analysis included 2-step and 1-step control logistic regression procedures.

Researchers found that each 5 kg/m2 increase in BMI was associated with elevated risk of colorectal cancer, more so, for men (OR, 1.26; 95% CI, 1.20-1.32; P =2.13 × 10-24) than for women (OR, 1.14; 95% CI, 1.11-1.18; P =9.75 × 10-17).  For women, the 2-step method identified a statistically significant interaction between BMI and a SMAD7 intronic variant (P =.0009). The Cocktail method did not identify any statistically significant interactions for men. In confirmation, a joint 2-degree of freedom test also revealed the statistically significant interaction between BMI and the same intronic variant for women (P =2.43 × 10-10). No such interaction was observed in men. Also, BMI per 5 kg·m2 was strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype of the SMAD7 variant (OR, 1.24; 95% CI, 1.16-1.32; P =2.60 × 10-10) than for women with other genotypes. No similar the multiplicative interaction was observed in men for the SMAD7 variant.

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Limitations of the study include the fact that relatively few participants who had tumor molecular phenotype data were included, the ability to discern specific tumor phenotypic profiles according to sex-specific strata, misreporting due to self-reporting, and lack of generalizability.

In conclusion, the researchers identified a novel association whereby a common variant in SMAD7 and BMI may jointly influence colorectal cancer risk in women, suggesting that well-established risk factor for colorectal cancer may interact with certain genetic variants.

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Reference

Campbell PT, Lin Y, Bien SA, Figueiredo JC, Harrison TA, Guinter MJ, et al. Association of body mass index with colorectal cancer risk by genome-wide variants (published online April 22, 2020). J Natl Cancer Inst. doi.org/10.1093/jnci/djaa058