The Role of Nuclear APOBEC Enzymes in Neoplastic Progression of Ulcerative Colitis

Lene Alsøe,1,2,* Stephan Andreas Brackmann,2,3,* Yan Liu,4 Anna Berit Wennerström,4 Qin Ying Esbensen,2,4 Sumana Kalyanasundaram,5 Yohan Lefol,2,6 Diana Domanska,2,7,8 Solveig Norheim Andersen,2 Hilde Loge Nilsen1,2,6 1Department of Microbiology, Oslo University Hospital, Oslo, Norway; 2Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 3Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway; 4Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway; 5Department of Informatics, University of Oslo, Oslo, Norway; 6CRESCO - Centre for Embryology and Healthy Development, University of Oslo, Oslo, Norway; 7Department of Pathology, Oslo University Hospital, Oslo, Norway; 8Faculty of Mathematics and Computer Science, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland*These authors contributed equally to this workCorrespondence: Hilde Loge Nilsen, Email [email protected] Stephan Andreas Brackmann, Email [email protected]: Aberrant expression of the cytidine DNA deaminase AID in enterocytes within inflamed mucosa in ulcerative colitis (UC) patients has been proposed to be involved in progression of UC to colitis-associated colorectal cancer (CA-CRC). Here, we followed the expression of AID and other nuclear cytidine DNA deaminases of the APOBEC family through several stages of progression of UC in a CA-CRC case (UC progressor) and in a cohort of UC progressors and non-progressors. In inflamed and high-grade dysplastic mucosa, AICDA and APOBEC1 mRNAs, but not APOBEC3-family enzyme mRNAs, were overexpressed compared to non-inflamed tissue. Immunohistochemical staining did not show expression of AID or APOBEC3 enzymes in the enterocytes, neither in specimens from the CA-CRC case nor in biopsies from the progressor and non-progressor cohort. APOBEC1 was highly expressed in the enterocytes throughout the colorectum from the CA-CRC case and in most biopsies examined from the progressor and non-progressor cohort. The expression was not correlated with the histology of the mucosa or the progression status of the patients. In the CA-CRC case, we identified AID- and APOBEC3-associated mutation signatures in inflamed, high-grade dysplasia and cancer genomes. In conclusion, our findings suggest that AID or other nuclear APOBECs are unlikely to drive the progression of UC to CA-CRC late during course of UC. However, we cannot exclude the possibility that bursts of AID and nuclear APOBEC3 activity may contribute to formation of genome instability in early phases of disease development.Keywords: inflammatory bowel disease, colorectal cancer, AID, genome instability, DNA damage response