CHEK2 germline variants in B-cell precursor acute lymphoblastic leukemia: findings in Mexican pediatric patients

Deleterious CHEK2 germline variants (GVs) are moderate-penetrance risk alleles that predispose individuals to adult-onset neoplasms. However, their association with childhood-onset cancers, such as B-cell precursor acute lymphoblastic leukemia (pre-B ALL), remains unexplored.

To describe the mutational profile of CHEK2 GVs in a cohort of Mexican children diagnosed with pre-B ALL and review the mutational landscape of CHEK2 GVs in children with pre-B ALL.

Next-generation exome sequencing was performed on 73 Mexican children with pre-B ALL. Clinical and genetic features of CHEK2 GVs carriers have been described. Associations between CHEK2 GVs and predisposition to pre-B ALL were evaluated using the MCPS population datasets as control groups. In addition, a literature review was conducted to investigate the potential link between CHEK2 germline variants and pre-B ALL. Finally, an in silico analysis was performed using bioinformatic tools and protein modeling to predict the functional and structural effects of these variants.

CHEK2 GVs were identified in four patients with high-risk pre-B ALL, two carried likely pathogenic variants (2.7%) and two carried variants of uncertain significance (2.7%). Three of these patients died due to disease progression, and two had a family history consistent with the CHEK2 cancer predisposition spectrum. Two unrelated cases carried the likely pathogenic CHEK2 p.Leu236Pro variant. When compared with the Indigenous Mexican stratum of the MCPS database, this variant was associated with pre-B ALL predisposition (unadjusted OR, 5.48; 95% CI, 1.34-22.37). Including previously reported cases, a total of 34 individuals with pre-B ALL carrying 20 distinct CHEK2 GVs were identified in the literature. Most variants were population-specific and predicted to impair protein function or structural stability. Structural modeling suggested that the recurrent CHEK2 p.Leu236Pro variant may introduce steric hindrance affecting protein dimerization.

Our findings and those described in the literature suggest that CHEK2 may play a role in the germline origin of childhood pre-B ALL in specific populations. However, this study provides preliminary evidence of pre-B ALL predisposition in Mexican children with CHEK2 GVs that needs replication in a larger cohort to obtain accurate estimations.