Obesity, sedentary behaviors, and diet quality for prevention and early detection of early-onset colorectal neoplasia

The rising incidence in early-onset colorectal cancer (CRC diagnosed before 50), has resulted in updated guidelines advising average-risk screening to begin at age 45. Debates centered around the substantial cost and resources of adding 21 million adults at very low risk to the screening pool, and “further personalize screening strategies” was a priority. Identifying the contributors of the rising incidence are the first steps but thus far an unmet need. Lifestyle factors that preceded and mirrored the rapid rise of early-onset CRC, including obesity, prolong sitting, and poor diet, may play a critical role. Our preliminary data support the importance of obesity and sedentary behaviors and early-onset CRC are more likely to be processed from traditional adenoma-carcinoma sequence compared to CRC diagnosed after age 65. Therefore, investigation into risk factors for early-onset advanced adenoma, the major targets of screening, will illuminate insights of colorectal carcinogenesis at younger ages. Accumulating data suggest that microbial translocation/endotoxemia, which triggers subsequent inflammation and immune response, and augmented by above-mentioned lifestyle factors, might be an emerging pathway. We hypothesized that obesity, prolonged sitting, and poor diet quality increase risk of early-onset advanced adenoma through increasing endotoxemia and inflammation, and contribute to the rise of early-onset CRC. To test these hypotheses, we will leverage lifestyle data collected throughout life course in two wellcharacterized prospective cohort (Nurses’ Health Study II [NHSII]) and Southern Community Cohort Study (SCCS) with archived pre-diagnostic blood, complemented by decision modeling using the Microsimulation Screening Analysis‐Colon (MISCAN‐Colon). In addition to risk factors, we will also elucidate the role of promising pharmacological agents for the prevention of early-onset CRC. We will also take a step further to conduct indepth interviews among stakeholders to set the stage for behavioral and molecularly driven intervention trials aiming to address the unique needs and challenges in prevention and early detection. Our interdisciplinary team, led by a leader in early-onset CRC etiology, and leaders in causal inference, biomarker measurement and discoveries, decision modeling, and qualitative research, offers unparalleled expertise. This investigation will illuminate significant insights into the etiology of early-onset CRC and will be a significant step forward to optimal/personalized prevention and early detection of early-onset CRC among younger adults.