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<p>The role of germline <i>CHEK2</i> variants in hematopoietic malignancies (HMs) is poorly understood. We examined pathogenic/likely pathogenic (P/LP) <i>CHEK2</i> 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 <i>CHEK2</i> variants, mostly p.I157T (53%, 30/57). Among <i>CHEK2</i> 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 <i>CHEK2</i> alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. <i>CHEK2</i> p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, <i>P</i> &lt; 0.001). In a solid tumor risk cohort, 36% (15/42) of <i>CHEK2</i> p.I157T patients had a HM family history. A genome wide association study showed enrichment of <i>CHEK2</i> loss-of-function variants with myeloid leukemia (<i>P</i> = 5.78e<sup>−7</sup>). In public acute myeloid leukemia (AML) datasets, 1% (16/1348) of patients had P/LP <i>CHEK2</i> variants. In a public myelodysplastic neoplasms (MDS) dataset, 2% (5/214) had P/LP <i>CHEK2</i> variants. <i>Chek2</i> p.I161T mice, homologous to human p.I157T, had worse survival as heterozygotes (<i>P</i> = 0.037) or homozygotes (<i>P</i> = 0.005), with fewer Lin-CD34+ and Lin-cKit+ cells. Our data suggest P/LP <i>CHEK2</i> variants are HHM risk alleles.</p>

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Predisposition to hematopoietic malignancies by deleterious germline CHEK2 variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月7日

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  • 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

摘要

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.