DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs.

Autor:	Guo H; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., Vuille JA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA., Wittner BS; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA., Lachtara EM; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA., Hou Y; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Lin M; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Zhao T; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Raman AT; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Russell HC; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA., Reeves BA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA., Pleskow HM; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA., Wu CL; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Gnirke A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Meissner A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany., Efstathiou JA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA., Lee RJ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Toner M; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Engineering in Medicine and Shriners Hospital for Children, Harvard Medical School, Boston, MA 02114, USA., Aryee MJ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Lawrence MS; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Miyamoto DT; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: dmiyamoto@mgh.harvard.edu., Maheswaran S; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: maheswaran@helix.mgh.harvard.edu., Haber DA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: dhaber@mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2023 Jun 22; Vol. 186 (13), pp. 2765-2782.e28. Date of Electronic Publication: 2023 Jun 15.
DOI:	10.1016/j.cell.2023.05.028
Abstrakt:	Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution genome-wide single-cell DNA methylation sequencing, we identify 40 core domains that are uniformly hypomethylated from the earliest detectable stages of prostate malignancy through metastatic circulating tumor cells (CTCs). Nested among these repressive domains are smaller loci with preserved methylation that escape silencing and are enriched for cell proliferation genes. Transcriptionally silenced genes within the core hypomethylated domains are enriched for immune-related genes; prominent among these is a single gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells and four IFI16-related interferon-inducible genes implicated in innate immunity. The re-expression of CD1 or IFI16 murine orthologs in immuno-competent mice abrogates tumorigenesis, accompanied by the activation of anti-tumor immunity. Thus, early epigenetic changes may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for CTCs. Competing Interests: Declaration of interests Massachusetts General Hospital (MGH) has applied for patents regarding the CTC-iChip technology and CTC detection signatures. M.T., S.M., and D.A.H. are cofounders and have equity in Tell-Bio, which is not related to this work. The interests of these authors were reviewed and managed by MGH and Mass General Brigham (MGB) in accordance with their conflict of interest policies. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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