V J Forster, M Aronson, C Zhang, J Chung, S Sudhaman, M A Galati, J Kelly, L Negm, A B Ercan, L Stengs, C Durno, M Edwards, M Komosa, L E Oldfield, N M Nunes, S Pedersen, J Wellum, I Siddiqui, V Bianchi, B R Weil, V L Fox, T J Pugh, J Kamihara, U Tabori
We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAMdel iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD...
March 11, 2024: NPJ Precision Oncology