Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth.

Autor: Ghantous A; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, (IARC), 25 avenue Tony Garnier, CS 90627, Lyon, Cedex 07 69366, France. GhantousA@iarc.who.int., Nusslé SG; Genknowme SA, Alanine Building, Corniche Road 5, 1066, Epalinges, Switzerland., Nassar FJ; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, (IARC), 25 avenue Tony Garnier, CS 90627, Lyon, Cedex 07 69366, France., Spitz N; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, (IARC), 25 avenue Tony Garnier, CS 90627, Lyon, Cedex 07 69366, France., Novoloaca A; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, (IARC), 25 avenue Tony Garnier, CS 90627, Lyon, Cedex 07 69366, France., Krali O; Department of Medical Sciences, Molecular Precision Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Nickels E; Center for Genetic Epidemiology, University of Southern California, Los Angeles, USA.; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, USA., Cahais V; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, (IARC), 25 avenue Tony Garnier, CS 90627, Lyon, Cedex 07 69366, France., Cuenin C; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, (IARC), 25 avenue Tony Garnier, CS 90627, Lyon, Cedex 07 69366, France., Roy R; Computational Biology and Informatics Core, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA., Li S; Center for Genetic Epidemiology, University of Southern California, Los Angeles, USA., Caron M; Department of Pediatrics, University of Montreal & Research Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Montréal, Quebec, Canada., Lam D; School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, 6009, Australia.; Harry Perkins Institute of Medical Research, Nedlands, Western Australia, 6009, Australia., Fransquet PD; Centre for Social and Early Emotional Development (SEED), School of Psychology, Deakin University, Burwood, Victoria, Australia., Casement J; Bioinformatics Support Unit, Newcastle University, Newcastle upon Tyne, UK., Strathdee G; Newcastle University Centre for Cancer, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK., Pearce MS; Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK., Hansen HM; Neuro and Molecular Epidemiology Laboratory, University of California San Francisco, San Francisco, USA., Lee HH; Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408, Korea., Lee YS; Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408, Korea., de Smith AJ; Center for Genetic Epidemiology, University of Southern California, Los Angeles, USA., Sinnett D; Department of Pediatrics, University of Montreal & Research Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Montréal, Quebec, Canada., Håberg SE; Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway., McKay JA; Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK., Nordlund J; Department of Medical Sciences, Molecular Precision Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Magnus P; Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway., Dwyer T; Clinical Sciences Theme, Heart Group, Murdoch Children's Research Institute, Melbourne, Australia.; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia., Saffery R; Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia., Wiemels JL; Center for Genetic Epidemiology, University of Southern California, Los Angeles, USA., Munthe-Kaas MC; Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.; Department of Pediatric Oncology and Hematology, Oslo University Hospital, Oslo, Norway., Herceg Z; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, (IARC), 25 avenue Tony Garnier, CS 90627, Lyon, Cedex 07 69366, France. HercegZ@iarc.who.int.
Jazyk: angličtina
Zdroj: Molecular cancer [Mol Cancer] 2024 Oct 23; Vol. 23 (1), pp. 238. Date of Electronic Publication: 2024 Oct 23.
DOI: 10.1186/s12943-024-02118-4
Abstrakt: Background: Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation.
Methods: Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations.
Results: The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues (n=5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression (n=2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation.
Conclusion: This study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy.
(© 2024. The Author(s).)
Databáze: MEDLINE
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