The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia.

Autor:	Hakkarainen M; Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Helsinki, Finland.; Department of Medical and Clinical Genetics/Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Kaaja I; Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Medical and Clinical Genetics/Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Douglas SPM; Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Medical and Clinical Genetics/Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Vulliamy T; Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom., Dokal I; Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London and Barts Health, London, United Kingdom., Soulier J; Hematology Laboratory and INSERM U944, Saint-Louis Hospital, University of Paris, Paris, France., Larcher L; Hematology Laboratory and INSERM U944, Saint-Louis Hospital, University of Paris, Paris, France., Peffault de Latour R; French Reference Center for Aplastic Anemia, BMT unit, Saint-Louis Hospital, Paris Cité University, Paris, France., Leblanc T; Department of Immunology and Pediatric Hematology, Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, URP3518 University Paris Cité, Paris, France., Sicre de Fontbrune F; French Reference Center for Aplastic Anemia, BMT unit, Saint-Louis Hospital, Paris Cité University, Paris, France., Siitonen T; Department of Medicine, Oulu University Hospital Cancer Center, Oulu, Finland., Lohi O; Tampere Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland., Hellström-Lindberg E; Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Huddinge, Sweden.; Department of Hematology, Karolinska University Hospital, Stockholm, Sweden., Barbany G; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden., Tesi B; Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Huddinge, Sweden.; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden., Shimamura A; Dana-Farber/Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA., Beier F; Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, RWTH Aachen University, Aachen, Germany.; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Aachen, Germany., Jackson S; Department of Haematology, Te Whatu Ora Health New Zealand Counties Manukau, Auckland, New Zealand., Kuperman AA; Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.; Blood Coagulation Service and Pediatric Hematology Clinic, Galilee Medical Center, Nahariya, Israel., Falik Zaccai T; Blood Coagulation Service and Pediatric Hematology Clinic, Galilee Medical Center, Nahariya, Israel., Tamary H; The Rina Zaizov Hematology-Oncology Division, Schneider Children's Medical Center of Israel, Petah Tikva, Israel., Mecucci C; Laboratorio di Citogenetica e Medicina Molecolare, Sezione di Ematologia ed Immunologia Clinica, Centro Ricerche Emato-Oncologiche, Università degli Studi di Perugia, Perugia, Italy., Capolsini I; Pediatric Oncohematology with Bone Marrow Transplant, S. Maria della Misericordia Hospital, Perugia, Italy., Jahnukainen K; Children's Hospital, and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland., Salmenniemi U; Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Helsinki, Finland., Niinimäki R; Department of Pediatrics, Oulu University Hospital and PEDEGO Research Unit, University of Oulu, Oulu, Finland., Varilo T; Department of Medical and Clinical Genetics/Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland., Kilpivaara O; Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Medical and Clinical Genetics/Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; HUS Diagnostic Center (Helsinki University Hospital), HUSLAB Laboratory of Genetics, University of Helsinki, Helsinki, Finland., Wartiovaara-Kautto U; Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Helsinki, Finland.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Jun 08; Vol. 141 (23), pp. 2853-2866.
DOI:	10.1182/blood.2022019425
Abstrakt:	Biallelic germ line excision repair cross-complementing 6 like 2 (ERCC6L2) variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies, characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germ line variants collected retrospectively from 11 centers globally, with a follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). The subjects presented with 19 different variants of ERCC6L2, and we identified a founder mutation, c.1424delT, in Finnish patients. The median age of the subjects at baseline was 18 years (range, 2-65 years). Changes in the complete blood count were mild despite severe bone marrow (BM) hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without HMs. Signs of progressive disease included increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in the BM morphology. The median age at the onset of HM was 37.0 years (95% CI, 31.5-42.5; range, 12-65 years). The overall survival (OS) at 3 years was 95% (95% CI, 85-100) and 19% (95% CI, 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome with a 3-year OS of 28% (95% CI, 0-61). Our results demonstrated the importance of early recognition and active surveillance in patients with biallelic germ line ERCC6L2 variants. (© 2023 by The American Society of Hematology.)
Databáze:	MEDLINE
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