International Journal of Molecular Sciences (May 2022)
Recurrent Germline Variant in <i>RAD21</i> Predisposes Children to Lymphoblastic Leukemia or Lymphoma
- Anne Schedel,
- Ulrike Anne Friedrich,
- Mina N. F. Morcos,
- Rabea Wagener,
- Juha Mehtonen,
- Titus Watrin,
- Claudia Saitta,
- Triantafyllia Brozou,
- Pia Michler,
- Carolin Walter,
- Asta Försti,
- Arka Baksi,
- Maria Menzel,
- Peter Horak,
- Nagarajan Paramasivam,
- Grazia Fazio,
- Robert J Autry,
- Stefan Fröhling,
- Meinolf Suttorp,
- Christoph Gertzen,
- Holger Gohlke,
- Sanil Bhatia,
- Karin Wadt,
- Kjeld Schmiegelow,
- Martin Dugas,
- Daniela Richter,
- Hanno Glimm,
- Merja Heinäniemi,
- Rolf Jessberger,
- Gianni Cazzaniga,
- Arndt Borkhardt,
- Julia Hauer,
- Franziska Auer
Affiliations
- Anne Schedel
- Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
- Ulrike Anne Friedrich
- Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
- Mina N. F. Morcos
- Department of Pediatrics, School of Medicine, Technical University of Munich; 80804 Munich, Germany
- Rabea Wagener
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Duesseldorf, Medical Faculty, 40225 Duesseldorf, Germany
- Juha Mehtonen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Yliopistonranta 1, FI-70211 Kuopio, Finland
- Titus Watrin
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Duesseldorf, Medical Faculty, 40225 Duesseldorf, Germany
- Claudia Saitta
- Tettamanti Research Center, Pediatrics, University of Milan Bicocca, Fondazione MBBM/San Gerardo Hospital, 20900 Monza, Italy
- Triantafyllia Brozou
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Duesseldorf, Medical Faculty, 40225 Duesseldorf, Germany
- Pia Michler
- Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
- Carolin Walter
- Institute of Medical Informatics, University of Muenster, 48149 Muenster, Germany
- Asta Försti
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
- Arka Baksi
- Institute of Physiological Chemistry, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
- Maria Menzel
- Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
- Peter Horak
- Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Nagarajan Paramasivam
- Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
- Grazia Fazio
- Tettamanti Research Center, Pediatrics, University of Milan Bicocca, Fondazione MBBM/San Gerardo Hospital, 20900 Monza, Italy
- Robert J Autry
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
- Stefan Fröhling
- Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Meinolf Suttorp
- Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
- Christoph Gertzen
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Duesseldorf, Universitätsstraße 1, 40225 Duesseldorf, Germany
- Holger Gohlke
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Duesseldorf, Universitätsstraße 1, 40225 Duesseldorf, Germany
- Sanil Bhatia
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Duesseldorf, Medical Faculty, 40225 Duesseldorf, Germany
- Karin Wadt
- Department of Clinical Genetics, University Hospital of Copenhagen, Faculty of health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- Kjeld Schmiegelow
- Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark
- Martin Dugas
- Institute of Medical Informatics, University of Muenster, 48149 Muenster, Germany
- Daniela Richter
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, 01307 Dresden, Germany
- Hanno Glimm
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, 01307 Dresden, Germany
- Merja Heinäniemi
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Yliopistonranta 1, FI-70211 Kuopio, Finland
- Rolf Jessberger
- Institute of Physiological Chemistry, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
- Gianni Cazzaniga
- Tettamanti Research Center, Pediatrics, University of Milan Bicocca, Fondazione MBBM/San Gerardo Hospital, 20900 Monza, Italy
- Arndt Borkhardt
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Duesseldorf, Medical Faculty, 40225 Duesseldorf, Germany
- Julia Hauer
- Department of Pediatrics, School of Medicine, Technical University of Munich; 80804 Munich, Germany
- Franziska Auer
- Department of Pediatrics, School of Medicine, Technical University of Munich; 80804 Munich, Germany
- DOI
- https://doi.org/10.3390/ijms23095174
- Journal volume & issue
-
Vol. 23,
no. 9
p. 5174
Abstract
Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.
Keywords
- acute lymphoblastic leukemia
- trio sequencing
- germline cancer predisposition
- <i>RAD21</i>
- cohesin complex
