Predisposition to hematopoietic malignancies by deleterious germline CHEK2 variants
Ryan J. Stubbins, Stephen Arnovitz, Jennie Vagher, Anase Asom, Melody Perpich, Madeline Pies, Imo J. Akpan, Edward Chew, Joshua Bridgers, Aly Karsan, Courtnee V. Rodgers, Ashwin Koppayi, Hatice Basdag, Michael W. Drazer, Soma Das, Jason X. Cheng, Afaf E.G. Osman, Lucy A. Godley
Abstract
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.