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Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower-risk myelodysplastic syndromes

D. Rombaut, S. Sandmann, T. Tekath, S. Crouch, AO. de Graaf, A. Smith, D. Painter, O. Kosmider, M. Tobiasson, A. Lennartsson, BA. van der Reijden, S. Park, M. D'Aveni, B. Slama, E. Clappier, P. Fenaux, L. Adès, A. van de Loosdrecht, S....

. 2025 ; 9 (1) : e70073. [pub] 20250122

Status not-indexed Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25008589

Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.

Center for Hematology and Regenerative Medicine Department of Medicine Huddinge Karolinska Institute Karolinska University Hospital Stockholm Sweden

Clinic of Hematology Clinical Center of Vojvodina Faculty of Medicine University of Novi Sad Novi Sad Serbia

Department of Biosciences and Nutrition Karolinska Institute Stockholm Sweden

Department of Clinical Hematology Institute of Hematology and Blood Transfusion Prague Czech Republic

Department of Computational Biology Institut Gustave Roussy INSERM U981 Villejuif France

Department of Hematology Amsterdam UMC Cancer Center Amsterdam Amsterdam The Netherlands

Department of Hematology Oncology and Clinical Immunology Heinrich Heine University Medical Faculty Düsseldorf Germany

Department of Hematology Radboud University Medical Center Nijmegen The Netherlands

Department of Hematology Université de Grenoble Alpes CHU Grenoble France

Department of Internal Medicine 5 Comprehensive Cancer Center Innsbruck Medical University of Innsbruck Innsbruck Austria

Department of Laboratory Medicine Laboratory of Hematology Radboud University Medical Center Nijmegen The Netherlands

Department of Molecular Biology Faculty of Science Radboud University Nijmegen The Netherlands

Department of Molecular Medicine and Department of Hematology Oncology University of Pavia and Fondazione IRCCS Policlinico S Matteo Pavia Italy

Department of Tumor Immunology Radboud Institute of Molecular Life Sciences Radboud University Medical Center Nijmegen The Netherlands

Epidemiology and Cancer Statistics Group Department of Health Sciences University of York York UK

Hematology Division Department of Internal Medicine University of Patras Patras Greece

Institute of Medical Informatics University of Heidelberg Heidelberg Germany

Institute of Medical Informatics University of Münster Münster Germany

Laboratoire d'hématologie Centre Hospitalier Régional Universitaire Lille France

Service d'Hématologie Clinique University Hospital of Nancy and University of Lorraine Nancy France

Service d'onco hématologie Centre Hospitalier Général d'Avignon Avignon France

St James's Institute of Oncology Leeds Teaching Hospitals Leeds UK

Université Paris Cité Assistance Publique des Hôpitaux de Paris Nord Laboratoire d'Hématologie Hôpital Saint Louis Paris France

Université Paris Cité Assistance Publique des Hôpitaux de Paris Nord Service d'Hématologie Senior Hôpital Saint Louis Paris France

Université Paris Cité Institut Cochin INSERM U1016 CNRS UMR8104 Assistance Publique Hôpitaux de Paris Centre Laboratory of Hematology Hôpital Cochin Paris France

References provided by Crossref.org

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$a Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower-risk myelodysplastic syndromes / $c D. Rombaut, S. Sandmann, T. Tekath, S. Crouch, AO. de Graaf, A. Smith, D. Painter, O. Kosmider, M. Tobiasson, A. Lennartsson, BA. van der Reijden, S. Park, M. D'Aveni, B. Slama, E. Clappier, P. Fenaux, L. Adès, A. van de Loosdrecht, S. Langemeijer, A. Symeonidis, J. Čermák, C. Preudhomme, A. Savic, U. Germing, R. Stauder, D. Bowen, C. van Marrewijk, E. Bernard, T. de Witte, J. Varghese, E. Hellström-Lindberg, M. Dugas, J. Martens, L. Malcovati, JH. Jansen, M. Fontenay, MDS‐RIGHT consortium
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$a Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.
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