Genetic evidence for predisposition to acute leukemias due to a missense mutation (p.Ser518Arg) in ZAP70 kinase: a case-control study

• Published in: BMC medical genomics 2024-08, Vol.17 (1), p.200-10, Article 200
• Main Authors: Khashei Varnamkhasti, Khalil, Khashei Varnamkhasti, Samire, Shahrouzian, Atefeh, Rahimzadeh, Masoomeh, Naeimi, Leila, Naeimi, Behrouz, Naeimi, Sirous
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Acute myeloid leukemia; Adolescent; Adult; Amino acid substitution; Amino acids; Analysis; Blood tests; Case-Control Studies; Disease susceptibility; DNA sequencing; Equilibrium; Ethylenediaminetetraacetic acid; Female; Flow cytometry; Gene mutations; Genes; Genetic aspects; Genetic Predisposition to Disease; Genotype; Genotype & phenotype; Genotypes; Health aspects; Hematology; Humans; Kinases; Leukemia; Leukemia, Myeloid, Acute - genetics; Lymphatic leukemia; Male; Medical prognosis; Medical research; Medicine, Experimental; Middle Aged; Missense mutation; Mixed phenotype acute leukemia; Mutation; Mutation, Missense; Nucleotide sequencing; Phenotypes; Phenotypic variations; Physiological aspects; Polymerase chain reaction; Polymorphism; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Protein kinases; Proteins; Risk factors; rs104893674 (C > A); Sample size; Thermal cycling; Young Adult; ZAP-70 protein; ZAP-70 Protein-Tyrosine Kinase - genetics; ZAP70 gene
• ISSN: 1755-8794; 1755-8794
• DOI: 10.1186/s12920-024-01961-0

The apparent lack of additional missense mutations data on mixed-phenotype leukemia is noteworthy. Single amino acid substitution by these non-synonymous single nucleotide variations can be related to many pathological conditions and may influence susceptibility to disease. This case-control study aimed to unravel whether the ZAP70 missense variant (rs104893674 (C > A)) underpinning mixed-phenotype leukemia. The rs104893674 was genotyped in clients who were mixed-phenotype acute leukemia-, acute lymphoblastic leukemia- and acute myeloid leukemia-positive and matched healthy controls, which have been referred to all major urban hospitals from multiple provinces of country- wide, IRAN, from February 11' 2019 to June 10' 2023, by amplification refractory mutation system-polymerase chain reaction method. Direct sequencing for rs104893674 of the ZAP70 gene was performed in a 3130 Genetic Analyzer. We found that the AC genotype of individuals with A allele at this polymorphic site (heterozygous variant-type) contribute to the genetic susceptibility to acute leukemia of both forms, acute myeloid leukemia and acute lymphoblastic leukemia as well as with a mixed phenotype. In other words, the ZAP70 missense variant (rs104893674 (C > A)) increases susceptibility of distinct cell populations of different (myeloid and lymphoid) lineages to exhibiting cancer phenotype. The results were all consistent with genotype data obtained using a direct DNA sequencing technique. Of special interest are pathogenic missense mutations, since they generate variants that cause specific molecular phenotypes through protein destabilization. Overall, we discovered that the rs104893674 (C > A) variant chance in causing mixed-phenotype leukemia is relatively high.