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 germline aberration at amino...
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Published in | International journal of molecular sciences Vol. 23; no. 9; p. 5174 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
MDPI AG
05.05.2022
MDPI |
Subjects | |
Online Access | Get full text |
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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
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
p.P298S/A did not disrupt the formation of the cohesin complex, it altered
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
expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that
germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1422-0067 1661-6596 1422-0067 |
DOI: | 10.3390/ijms23095174 |