Abstract The current rise in early-onset colorectal cancer (EOCRC) has been attributed to a Westernized lifestyle, but a definitive lifestyle factor or genetic etiology has yet to be discovered. Still, genetic studies do show that APC mutations are initiating events in both EOCRC and later-onset CRC (LOCRC). So, a key question is why do somatic APC mutations occur at a relatively young age in EOCRC patients? Hence, we surmise that something is retarding tissue renewal in colonic crypts so that somatic mutations are retained instead of being extruded during tissue turnover. Thus, we conjecture that EOCRC involves an essential nutrient required for tissue renewal. Accordingly, we investigated vitamin A (retinol, retinoic acid), which is an essential vitamin requiring adequate dietary intake. Indeed, vitamin A is essential for tissue homeostasis because germline mutations in retinoid receptors and vitamin A deficiency during pregnancy can lead to fetal malformations. Moreover, population-based studies report vitamin A deficiency in pre-school-aged children. Consequently, young-aged individuals might be prone to cancer-initiating effects of vitamin A deficient diets. Our Goal is to determine how aberrant retinoid receptor expression might promote EOCRC development through dysregulated retinoic acid signaling. Rationale: Our previous studies show that retinoic acid (RA) signaling pathway plays an essential role in regulating cell differentiation in the colon. Moreover, we reported that CRC cells harboring mutations in RA receptors (RAR, RXR) have drug resistance to all-trans RA (ATRA). So, mutation or aberrant expression of RA receptors could lead to incomplete differentiation and promote CRC initiation. Hypothesis: Aberrant RA receptor expression leads to dysregulated RA signaling that contributes to EOCRC development. Results: Our bioinformatics analyses show that retinoid receptors are often abnormally expressed and mutated in human CRCs. We found that up to 22% of CRCs have RA receptor mutations, but mutation status did not predict patient survival. However, we did find that frequency of retinoid receptor mutation was higher (2X-fold) in EOCRC (age 45) compared to LOCRC. Specifically, a high frequency of somatic mutations (2x-fold) occurred in receptors for vitamin A (STRA6) and retinoic acid (RARG, PPARG) in EOCRCs. We also found RARG hypermethylation occurs frequently in EOCRCs (p0. 05). Conclusions Since the rate of retinoid receptor alteration was increased in EOCRCs, aberrant RA signaling may be a predisposing factor for early CRC development and contribute to the etiology of EOCRCs. Based on this view, reduced retinoid signaling could lead to incomplete differentiation which provides a mechanism that may explain how delayed tissue renewal causes retention of acquired APC mutations in colonic epithelium: Thus, we put forth the idea that aberrant vitamin A (retinol) metabolism and APC mutation-induced activation of WNT signaling are co-factors in promoting EOCRC. Citation Format: Bruce Boman, Brian Osmond, Anh Nguyen, Chi Zhang. Colonic Tissue Renewal, Retinoic Acid Signaling, Early-onset CRC abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr C004.
Boman et al. (Wed,) studied this question.