Emerging exposure-driven accelerated colorectal carcinogenesis: a model with implications for screening colonoscopy effectiveness.

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide, with its burden projected to rise. Screening average-risk individuals is recommended because several strategies reduced CRC incidence and mortality. While overall CRC incidence and mortality have stabilised or declined in many developed regions, rates increase in low- and middle-income countries, alongside a global surge in early-onset CRC (EOCRC). The previous shift toward earlier-stage diagnosis has reversed, with rising distal and rectal tumours, despite these being more amenable to prevention by screening. Even when performed with highest quality, guideline-concordant screening and surveillance cannot fully prevent CRC and post-colonoscopy CRC (PCCRC). These patterns suggest that current slowly progressing precursor-based models of tumourigenesis may not fully explain all emerging CRC phenotypes. We propose that sporadic microsatellite-stable EOCRC and a subset of PCCRC represent sentinel manifestations of a broader, under-recognised process of exposure-related accelerated carcinogenesis. In this conceptual model, environmental and lifestyle exposures may promote subclinical inflammation, immune dysregulation, microbiome disruption and epigenetic remodelling, thereby compressing the timeline from early mutational events to overt tumourigenesis. We postulate that cumulative exposures converge to create biologically permissive tissue states that enable accelerated malignant transition, either through shortened, subtle precursor phases or directly from dysplastic mucosa. We introduce oncoembryonic reprogramming as a potential molecular mechanism linking exposure-driven mucosal remodelling to accelerated tumour progression and malignant competence. This proposed model may help explain why some CRCs are not prevented by conventional precursor-based strategies and could have relevant implications for risk stratification, screening strategies and translational targeting.