Recurrent Germline Variant in <i>RAD21</i> Predisposes Children to Lymphoblastic Leukemia or Lymphoma
oleh: 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
| Format: | Article |
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| Diterbitkan: | MDPI AG 2022-05-01 |
Deskripsi
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 <i>RAD21</i> 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 <i>RAD21</i> p.P298S/A did not disrupt the formation of the cohesin complex, it altered <i>RAD21</i> 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 <i>RAD21</i> expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that <i>RAD21</i> germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.