Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition

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

doi:10.1038/s41698-024-00537-6

Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition

NPJ Precis Oncol. 2024 Mar 11;8(1):69. doi: 10.1038/s41698-024-00537-6.

Authors

V J Forster¹, M Aronson², C Zhang¹, J Chung¹, S Sudhaman¹, M A Galati¹, J Kelly¹, L Negm¹, A B Ercan¹, L Stengs¹, C Durno³, M Edwards¹, M Komosa¹, L E Oldfield⁴, N M Nunes¹, S Pedersen⁴, J Wellum⁴, I Siddiqui⁵, V Bianchi¹, B R Weil^{6

7}, V L Fox⁸, T J Pugh⁴, J Kamihara⁷, U Tabori^{9

10

11}

Affiliations

¹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
² Zane Cohen Centre, Sinai Health System and Faculty of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
³ Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ University Health Network, Toronto, ON, Canada.
⁵ Department of Paediatric Laboratory Medicine and Pathobiology, Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
⁹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
¹⁰ Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
¹¹ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. [email protected].

Abstract

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 EPCAM^del 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. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients.

Abstract

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