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2 results on '"T. J. Pugh"'

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

Author

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, and U. Tabori

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

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.

Published
2024
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2. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

Author

Stephen C. Mack, Kenneth Aldape, Karin M. Muraszko, James T. Rutka, Livia Garzia, Scott L. Pomeroy, Wiesława Grajkowska, Caretha L. Creasy, Till Milde, Marcel Kool, Joanna J. Phillips, Pedro Castelo-Branco, Martin Hirst, Jan Koster, Andrey Korshunov, David Malkin, Mathieu Lupien, Theophilos Tzaridis, Xiaochong Wu, Xiaoyang Zhang, Peter Lichter, Peter B. Dirks, Loretta Lau, Sharad K. Verma, Sergio L. Pereira, Andreas E. Kulozik, Gary D. Bader, Adrian M. Dubuc, K. Nethery-Brokx, Luca Massimi, Rosario M. Piro, Uri Tabori, T. Van Meter, Jennifer Zuccaro, Hendrik Witt, Ian D. Clarke, Martin Sill, David T.W. Jones, Sonja Hutter, Khalida Wani, Scott Zuyderduyn, Marina Ryzhova, L. Gu, Eric Bouffet, Mark Barszczyk, T. J. Pugh, Patrick Sin-Chan, Renee Head, Sameer Agnihotri, Roland Eils, Paul Kongkham, Adrian M. Stütz, Daniel W. Fults, John Peacock, Kelsey C. Bertrand, Sebastian Bender, Olaf Witt, Pascal Johann, Paul A. Northcott, Boleslaw Lach, Thomas Zichner, Sebastian Stark, Annie Huang, Marc Remke, Natalie Jäger, Huriye Seker-Cin, Cynthia Hawkins, Yuan Yao, Marco Gallo, Kory Zayne, Xin Wang, Claudia C. Faria, Volker Hovestadt, Xing Fan, Nalin Gupta, Michael D. Taylor, Stefan M. Pfister, Swneke D. Bailey, Yoon Jae Cho, Florence M.G. Cavalli, William A. Weiss, Marco A. Marra, Jan O. Korbel, Stephen W. Scherer, Nada Jabado, Stephen S. Roberts, A. von Deimling, David Shih, Vijay Ramaswamy, Graduate School, Oncogenomics, and Other departments

Subjects
Regulation of gene expression, Multidisciplinary, CpG Island Methylator Phenotype, NF-kappa B, Transcription Factor RelA, Proteins, Hindbrain, Biology, Article, Epigenesis, Genetic, Cell Transformation, Neoplastic, CpG site, Ependymoma, Immunology, DNA methylation, Cancer research, Animals, Humans, Pediatric ependymoma, CpG Islands, Female, Epigenetics, Epigenomics, Signal Transduction
Abstract

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Published
2014

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