Distinct somatic mutation profiles in colon cancer by behavioral comorbidity

Tobacco use, obesity, and type 2 diabetes are risk factors for colorectal cancer, but whether they generate distinct tumor mutation patterns is unclear. Tobacco is a known mutagen, while obesity and diabetes may act through metabolic and inflammatory pathways.

We analyzed colon cancer patients from the University of California Health Data Warehouse, linking clinical sequencing data to diagnosis-based indicators of tobacco dependence, obesity, and type 2 diabetes. For each gene-behavior pair, we conducted reverse logistic regressions and calculated a combined score reflecting the strength and specificity of association adjusting for demographic covariates and cancer stage. Multidimensional scaling and clustering assessed behavioral differentiation.

Of 981 gene-behavior tests, 87 pairs exhibited a behavioral association at p < 0.001 in adjusted models. Of these, 60 tobacco, 12 obesity, and 9 diabetes pairs had affinity ≥0.5; 48 tobacco pairs exceeded 1.0. Mean (SD) combined scores were 1.39 (0.79) for tobacco, 1.24 (0.88) for obesity, and 0.74 (0.39) for diabetes. Exemplars included KEAP1 and CDKN2A (tobacco), ASPSCR1 and PGR (obesity), and a smaller diabetes signal led by MAF.

Tobacco dependence is associated with a more mutagenic and distinct somatic mutation profile in colon cancer, suggesting fundamental differences in behavioral mechanisms of carcinogenesis.