Why Is Colorectal Cancer Occurring Earlier? Metabolic Dysfunction, Underrecognized Carcinogens, and Emerging Controversies
Abstract
PURPOSE OF THE REVIEW: Early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before 50 years of age, is increasing worldwide and represents a major challenge to current prevention and screening paradigms. While obesity and metabolic dysfunction are important contributors, EOCRC appears to arise from a complex interplay of genetic susceptibility, metabolic stress, early-life exposures, microbiome alterations, environmental factors, and potentially infectious agents. This review aims to critically examine recent epidemiologic, molecular, and multi-omics evidence on EOCRC etiology, integrate metabolic and exposomic hypotheses within a life-course framework, highlight ongoing controversies and methodological limitations, and discuss emerging challenges for risk stratification and prevention. RECENT FINDINGS: Recent EOCRC-specific meta-analyses and cohort studies demonstrate moderate associations between EOCRC and obesity, central adiposity, insulin resistance, metabolic syndrome, and lifestyle factors such as alcohol use, sedentary behavior, and ultra-processed diets. Molecular and multi-omics studies reveal that EOCRC is enriched for chromosomal instability–driven tumors, metabolic and inflammatory signaling pathways, gut microbiome dysbiosis, and accelerated epigenetic aging, exceeding chronological age by more than a decade in some patients. In utero exposures, early-life anthropometry and metabolic dysfunction may contribute to EOCRC risk, potentially…
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