TY  - JOUR
AU  - Schedel, Anne
AU  - Friedrich, Ulrike Anne
AU  - Morcos, Mina N F
AU  - Wagener, Rabea
AU  - Mehtonen, Juha
AU  - Watrin, Titus
AU  - Saitta, Claudia
AU  - Brozou, Triantafyllia
AU  - Michler, Pia
AU  - Walter, Carolin
AU  - Försti, Asta
AU  - Baksi, Arka
AU  - Menzel, Maria
AU  - Horak, Peter
AU  - Paramasivam, Nagarajan
AU  - Fazio, Grazia
AU  - Autry, Robert
AU  - Fröhling, Stefan
AU  - Suttorp, Meinolf
AU  - Gertzen, Christoph
AU  - Gohlke, Holger
AU  - Bhatia, Sanil
AU  - Wadt, Karin
AU  - Schmiegelow, Kjeld
AU  - Dugas, Martin
AU  - Richter, Daniela
AU  - Glimm, Hanno
AU  - Heinäniemi, Merja
AU  - Jessberger, Rolf
AU  - Cazzaniga, Gianni
AU  - Borkhardt, Arndt
AU  - Hauer, Julia
AU  - Auer, Franziska
TI  - Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma.
JO  - International journal of molecular sciences
VL  - 23
IS  - 9
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DKFZ-2022-00988
SP  - 5174
PY  - 2022
AB  - 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.
KW  - RAD21 (Other)
KW  - acute lymphoblastic leukemia (Other)
KW  - cohesin complex (Other)
KW  - germline cancer predisposition (Other)
KW  - trio sequencing (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:35563565
DO  - DOI:10.3390/ijms23095174
UR  - https://inrepo02.dkfz.de/record/179939
ER  -