Relationship between myeloid skewing and colorectal cancer risk in the Framingham Heart Study

Introduction: Differential regulation of myelopoiesis may contribute to divergent colorectal cancer (CRC) risk profiles associated with obesity and physical activity; however, this relationship has not been examined in humans. This study explored the relationship between myeloid skewing (monocyte-to-lymphocyte ratio), physical activity, obesity, and CRC risk in a retrospective cohort. Methods: From the Framingham study cohort, myeloid skewing was compared across BMI categories, waist circumference quartiles, and physical activity index (PAI) quintiles. Among participants who eventually received a CRC diagnosis, Cox proportional hazards models evaluated baseline circulating myeloid skewing as a predictor of incident CRC, adjusted for covariates. Results: Within the total study population (n = 5037), myeloid skewing increased across BMI categories, and waist circumference quartiles (P <.001), and decreased in the highest vs lowest PAI (P <.01). In the predictive cohort (non-CRC, n = 818; CRC, n = 16), continuous Cox models (per 1-SD increase in myeloid skewing) showed hazard ratios (HR) ranging from 1.08 to 1.37. Associations were statistically significant in BMI, waist circumference, BMI and waist circumference, PAI, diabetes, sex, and smoking adjusted models (HRs 1.30-1.37; P <.05), but were attenuated and not statistically significant in age, age and sex, and medication adjusted models (HRs 1.08-1.28; P >.05). Discussion: Obesity and lower physical activity were associated with higher myeloid skewing, and higher myeloid skewing was associated with increased incident CRC hazard across several adjusted Cox models. These findings highlight myeloid skewing as a candidate marker linking adiposity and physical inactivity to CRC risk and justify prospective validation in larger cohorts.