| Title: | Predisposition to hematopoietic malignancies by deleterious germline CHEK2 variants |
| Journal: | Leukemia |
| Published: | 7 May 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40335619/ |
| DOI: | https://doi.org/10.1038/s41375-025-02635-1 |
| URL: | https://www.nature.com/articles/s41375-025-02635-1.pdf |
Publication 15413
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Abstract
The role of germline CHEK2 variants in hematopoietic malignancies (HMs) is poorly understood. We examined pathogenic/likely pathogenic (P/LP) CHEK2 variants in patients with hereditary HMs (HHMs), a solid tumor risk cohort, public datasets, and a knock-in mouse model. In the HHM cohort, 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68-10.73, P < 0.001). In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history. A genome wide association study showed enrichment of CHEK2 loss-of-function variants with myeloid leukemia (P = 5.78e−7). In public acute myeloid leukemia (AML) datasets, 1% (16/1348) of patients had P/LP CHEK2 variants. In a public myelodysplastic neoplasms (MDS) dataset, 2% (5/214) had P/LP CHEK2 variants. Chek2 p.I161T mice, homologous to human p.I157T, had worse survival as heterozygotes (P = 0.037) or homozygotes (P = 0.005), with fewer Lin-CD34+ and Lin-cKit+ cells. Our data suggest P/LP CHEK2 variants are HHM risk alleles.</p>
12 Keywords
- Adult
- Aged
- Animals
- Checkpoint Kinase 2
- Female
- Genetic Predisposition to Disease
- Germ-Line Mutation
- Hematologic Neoplasms
- Humans
- Male
- Mice
- Middle Aged
18 Authors
- Ryan J. Stubbins
- Stephen Arnovitz
- Jennie Vagher
- Anase Asom
- Melody Perpich
- Madeline Pies
- Imo J. Akpan
- Edward Chew
- Joshua Bridgers
- Aly Karsan
- Courtnee Rodgers
- Ashwin Koppayi
- Hatice Basdag
- Michael W. Drazer
- Soma Das
- Jason Cheng
- Afaf E. G. Osman
- Lucy A. Godley
1 Application
| Application ID | Title |
|---|---|
| 83200 | Germline predisposition to hematopoietic malignancies |
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