Journal Article

DKFZ-2022-00988

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma.

Schedel, A. ; Friedrich, U. A. ; Morcos, M. N. F. ; Wagener, R. ; Mehtonen, J. ; Watrin, T. ; Saitta, C. ; Brozou, T. ; Michler, P. ; Walter, C. ; Försti, A.DKFZ* ; Baksi, A. ; Menzel, M. ; Horak, P.DKFZ* ; Paramasivam, N. ; Fazio, G. ; Autry, R.DKFZ* ; Fröhling, S.DKFZ* ; Suttorp, M. ; Gertzen, C. ; Gohlke, H. ; Bhatia, S. ; Wadt, K. ; Schmiegelow, K. ; Dugas, M. ; Richter, D.DKFZ* ; Glimm, H.DKFZ* ; Heinäniemi, M. ; Jessberger, R. ; Cazzaniga, G. ; Borkhardt, A. ; Hauer, J.DKFZ* ; Auer, F.

2022
Molecular Diversity Preservation International Basel

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Please use a persistent id in citations: doi:10.3390/ijms23095174

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.

Keyword(s): RAD21 ; acute lymphoblastic leukemia ; cohesin complex ; germline cancer predisposition ; trio sequencing

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)
3. Translationale Medizinische Onkologie (B340)
4. DKTK DD zentral (DD01)
5. DKTK MU LMU zentral (MU01)
6. B280 Translationale funktionelle Krebsgenomik (B280)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2022

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