Schedel, Anne; Friedrich, Ulrike Anne; Morcos, Mina N F; Wagener, Rabea; Mehtonen, Juha; Watrin, Titus; Saitta, Claudia; Brozou, Triantafyllia; Michler, Pia; Walter, Carolin; Försti, Asta; Baksi, Arka; Menzel, Maria; Horak, Peter; Paramasivam, Nagarajan; Fazio, Grazia; Autry, Robert J; Fröhling, Stefan; Suttorp, Meinolf; Gertzen, Christoph; Gohlke, Holger; Bhatia, Sanil; Wadt, Karin; Schmiegelow, Kjeld; Dugas, Martin; Richter, Daniela; Glimm, Hanno; Heinäniemi, Merja; Jessberger, Rolf; Cazzaniga, Gianni; Borkhardt, Arndt; Hauer, Julia; Auer, Franziska     «

Schedel, Anne; Friedrich, Ulrike Anne; Morcos, Mina N F; Wagener, Rabea; Mehtonen, Juha; Watrin, Titus; Saitta, Claudia; Brozou, Triantafyllia; Michler, Pia; Walter, Carolin; Försti, Asta; Baksi, Arka; Menzel, Maria; Horak, Peter; Paramasivam, Nagarajan; Fazio, Grazia; Autry, Robert J; Fröhling, Stefan; Suttorp, Meinolf; Gertzen, Christoph; Gohlke, Holger; Bhatia, Sanil; Wadt, Karin; Schmiegelow, Kjeld; Dugas, Martin; Richter, Daniela; Glimm, Hanno; Heinäniemi, Merja; Jessberger, Rolf; Cazzaniga...     »

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.      «

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...     »