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Cancer Cell. 2019 Feb 11;35(2):315-328.e6. doi: 10.1016/j.ccell.2019.01.005.

Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and BrafV600E-Induced Tumorigenesis.

Author information

1
CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA.
2
Hopkins Conte Digestive Disease, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3
Division of Biostatistics & Bioinformatics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
4
Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Unit 853, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
5
Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19122, USA.
6
Department of Human Genetics, Canadian Centre for Computational Genomics, McGill University, Montreal, QC, Canada.
7
Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China.
8
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
9
Germans Trias i Pujol Health Science Research Institute (IGTP), Program for Personalized Medicine of Cancer, Badalona, 08916 Catalonia, Spain.
10
CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA. Electronic address: sbaylin1@jhmi.edu.
11
CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA. Electronic address: heaswar1@jhmi.edu.

Abstract

We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by BrafV600E, producing the typical human proximal BRAFV600E-driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP). Conversely, CRISPR-mediated simultaneous inactivation of a panel of the silenced genes markedly sensitizes to BrafV600E-induced transformation. Our studies tightly link aging-like epigenetic abnormalities to intestinal cell fate changes and predisposition to oncogene-driven colon tumorigenesis.

KEYWORDS:

BRAF(V600E); CIMP; CpG-island DNA methylation; aging; cancer risk; colon adenocarcinomas; epigenetic silencing; transformation; tumor predisposition; tumorigenesis

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