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Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma
Anne Schedel1, Ulrike Anne Friedrich1, Mina N F Morcos2
1Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.
International Journal of Molecular Sciences
|May 14, 2022
Summary
A new RAD21 gene variant (p.P298S/A) was found in children with leukemia or lymphoma. This germline mutation may predispose individuals to childhood cancers without causing Cornelia-de-Lange syndrome (CdLS).
Area of Science:
- Genetics
- Oncology
- Cell Biology
Background:
- Somatic mutations in cohesin genes are linked to cancers.
- Germline cohesin disruption causes cohesinopathies like Cornelia-de-Lange syndrome (CdLS).
Purpose of the Study:
- To investigate the role of a specific RAD21 germline aberration in pediatric cancer.
- To determine if this aberration predisposes to lymphoblastic leukemia or lymphoma.
Main Methods:
- Identified RAD21 p.P298S/A variant in pediatric cancer patients.
- Assessed cohesin complex formation, RAD21 gene expression, and DNA damage response.
- Analyzed patient fibroblasts and healthy bone marrow using single-cell RNA-sequencing.
Main Results:
- A recurrent heterozygous RAD21 germline aberration (p.P298S/A) was found in 3/482 pediatric cancer patients.
- The variant did not disrupt cohesin complex formation but altered RAD21 expression and DNA damage response.
- Patient fibroblasts showed increased G2/M arrest post-irradiation and Mitomycin-C treatment.
- Single-cell RNA-sequencing revealed distinct cohesin gene patterns during hematopoiesis, especially in B- and T-cells.
Conclusions:
- Germline RAD21 variants, like p.P298S/A, may predispose to childhood lymphoblastic leukemia or lymphoma.
- This predisposition can occur without the typical phenotype of Cornelia-de-Lange syndrome (CdLS).
- RAD21 expression is critical for hematopoiesis, particularly in proliferating lymphocytes.
Keywords:
RAD21acute lymphoblastic leukemiacohesin complexgermline cancer predispositiontrio sequencingMore Related Videos
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