Abstract P83: LOW DOSE MEDICAL DIAGNOSTIC RADIATION, A RISK FACTOR FOR COLON CARCINOGENESIS?

Abstract

Every day, 500 000 patients worldwide undergo radiological examinations using CT scans. These procedures account for nearly 75% of the collective effective dose received by patients. The associated cancer risk is particularly relevant for colon cancer, where a dose/risk relationship has been demonstrated at exposures below 1Gy. Recent studies suggest that low-dose radiation (LDR) can impact cancer stem cells, cell cycle regulation, reactive oxygen species production, and DNA methylation. However, these events have yet to be mechanistically linked. To address this gap, we investigated the effects of radiation from medical diagnostic procedures at physiological, cellular and molecular levels. We first characterized and validated the B6.Cg-Krastm4Tyj Apctm1Tno Tg(CDX2-cre/ERT2)752Erf/MaraJ mouse model, referred to as KPC:APC (Maitra et al., 2019), which recapitulates colon carcinogenesis via the chromosomal instability pathway through inducible Apc and Kras mutations. Following tamoxifen induction, mice develop hyperplastic and dysplastic lesions of the colonic epithelium, along with adenomas. From this model, we established a novel KPC:APC inducible organoid system faithfully recapitulating colon carcinogenesis in vitro. Both models were exposed to 25 or 250 mGy X-rays under conditions simulating CT scans, either during the initiation or the progression stages of carcinogenesis. Our results demonstrate that LDR during the initiation phase differentially affects the colonic epithelium depending on its mutational status. In the absence of the Kras mutation, no significant changes were observed in lesion distribution or organoid phenotype. However, in the presence of both Apc and Kras mutations, LDR significantly increased the number of pre-cancerous lesions and the size of tumoroids. Transcriptomic and proteomic analyses corroborated these findings, revealing a genotype-specific molecular response to radiation. In conclusion, our study shows that medical diagnostic radiation may promote colon carcinogenesis in genetically predisposed models, providing new insights into the risks associated with medical imaging and the molecular mechanisms underlying colon carcinogenesis.