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Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition.
Forster, V J; Aronson, M; Zhang, C; Chung, J; Sudhaman, S; Galati, M A; Kelly, J; Negm, L; Ercan, A B; Stengs, L; Durno, C; Edwards, M; Komosa, M; Oldfield, L E; Nunes, N M; Pedersen, S; Wellum, J; Siddiqui, I; Bianchi, V; Weil, B R; Fox, V L; Pugh, T J; Kamihara, J; Tabori, U.
Affiliation
  • Forster VJ; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Aronson M; Zane Cohen Centre, Sinai Health System and Faculty of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • Zhang C; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Chung J; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Sudhaman S; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Galati MA; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Kelly J; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Negm L; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Ercan AB; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Stengs L; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Durno C; Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada.
  • Edwards M; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Komosa M; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Oldfield LE; University Health Network, Toronto, ON, Canada.
  • Nunes NM; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Pedersen S; University Health Network, Toronto, ON, Canada.
  • Wellum J; University Health Network, Toronto, ON, Canada.
  • Siddiqui I; Department of Paediatric Laboratory Medicine and Pathobiology, Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
  • Bianchi V; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • Weil BR; Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
  • Fox VL; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Pugh TJ; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
  • Kamihara J; University Health Network, Toronto, ON, Canada.
  • Tabori U; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
NPJ Precis Oncol ; 8(1): 69, 2024 Mar 11.
Article in En | MEDLINE | ID: mdl-38467830
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 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. 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: NPJ Precis Oncol Year: 2024 Document type: Article Affiliation country: Canadá
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: NPJ Precis Oncol Year: 2024 Document type: Article Affiliation country: Canadá