The role of tissue renewal in early-onset colorectal cancer

A genetic etiology hasn't been discovered yet for early-onset CRC (EOCRC). An essential question is why do somatic APC mutations occur at a relatively young age in EOCRC patients? Indeed, APC mutations are the initiating event in both EOCRC and later-onset CRC (LOCRC). Moreover, most other cancer types frequently have inactivated APC due to promoter hypermethylation. However, we didn't find that other early onset cancer types (age <50) have increased APC hypermethylation. So, for EOCRC, we surmise that something is retarding tissue renewal such that cells with acquired APC mutations are retained instead of being extruded during tissue turnover. We conjectured that EOCRC involves an essential nutrient required for tissue renewal. Accordingly, we investigated the seven essential vitamins that require adequate dietary intake. Indeed, these vitamins are essential for tissue homeostasis because germline mutations in their receptors cause birth defects. Our bioinformatics analysis shows a high frequency of somatic mutations (2x-fold) in receptors for vitamin A (STRA6 ), and retinoic acid ( RARG , PPARG ) in EOCRCs (<45) vs . LOCRCs. We also found RARG hypermethylation occurs frequently in EOCRCs (p<0.05). Moreover, population-based studies report relatively frequent vitamin A deficiency in pre-school-aged children. Consequently, young-aged individuals might be prone to any cancer-initiating effects of vitamin A deficient diets. Indeed, vitamin A plays a crucial role in cell differentiation, particularly in the differentiation of stem cells and during tissue regeneration. Thus, incomplete differentiation of crypt cells due to reduced retinoic acid signaling may provide a mechanism that explains how delayed tissue renewal causes retention of somatic APC mutations in colonic epithelium. Thus, we put forth the hypothesis that aberrant vitamin A (retinol) metabolism and APC mutation-induced activation of WNT signaling are co-factors in promoting EOCRC.