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Recurrent germline variant in RAD21 predisposes children to lymphoblastic leukemia or lymphoma

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...

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Main Authors: Schedel, Anne (Author) , Friedrich, Ulrike Anne (Author) , Morcos, Mina N. F. (Author) , Wagener, Rabea (Author) , Mehtonen, Juha (Author) , Watrin, Titus (Author) , Saitta, Claudia (Author) , Brozou, Triantafyllia (Author) , Michler, Pia (Author) , Walter, Carolin (Author) , Försti, Asta (Author) , Baksi, Arka (Author) , Menzel, Maria (Author) , Horak, Peter (Author) , Paramasivam, Nagarajan (Author) , Fazio, Grazia (Author) , Autry, Robert J. (Author) , Fröhling, Stefan (Author) , Suttorp, Meinolf (Author) , Gertzen, Christoph (Author) , Gohlke, Holger (Author) , Bhatia, Sanil (Author) , Wadt, Karin (Author) , Schmiegelow, Kjeld (Author) , Dugas, Martin (Author) , Richter, Daniela (Author) , Glimm, Hanno (Author) , Heinäniemi, Merja (Author) , Jessberger, Rolf (Author) , Cazzaniga, Gianni (Author) , Borkhardt, Arndt (Author) , Hauer, Julia Christina (Author) , Auer, Franziska (Author)
Format: Article (Journal)
Language:English
Published: 2022
In: International journal of molecular sciences
Year: 2022, Volume: 23, Issue: 9, Pages: 1-15
ISSN:1422-0067
DOI:10.3390/ijms23095174
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/ijms23095174
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/1422-0067/23/9/5174
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Author Notes: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 and Franziska Auer
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Summary: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.
Item Description:This article belongs to the Special Issue Genetics and Epigenetics in Complex Diseases
Gesehen am 27.06.2022
Physical Description:Online Resource
ISSN:1422-0067
DOI:10.3390/ijms23095174

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