Insights from Tissue Inhibitor of Metalloproteinase-2 Genotypes to Decipher the Genetic Architecture of Childhood Acute Lymphocytic Leukemia Risk

Acute lymphoblastic leukemia (ALL) is the most common pediatric hematologic malignancy, particularly affecting children aged 2~5 years. Tissue inhibitor of metalloproteinase-2 (TIMP-2), a key regulator of MMP-2 activity, has been implicated in several cancers, yet its genetic role in childhood ALL remains unexplored. This study investigated four TIMP-2 polymorphic genotypes, rs8179090, rs4789936, rs2009196, and rs7342880, in 266 Taiwanese children with ALL and 266 matched controls using polymerase chain reaction-restriction fragment length polymorphism methodology. TIMP-2 rs8179090 exhibited a significant association with ALL risk. Individuals with the CC genotype had a markedly increased risk [odds ratio (OR)=4.01, 95% confidence interval (CI)=1.46-11.04, p=0.0076], particularly under a recessive model (OR=3.79, 95%CI=1.39-10.36, p=0.0105). The C allele frequency was also elevated in cases (20.7%) versus controls (14.5%) (p=0.0100). Stratified analysis showed stronger risk association in children aged ≤3.5 years (CC genotype: OR=5.06, p=0.0084) and in boys (CC genotype: OR=5.53, p=0.0046). Moreover, CG+CC genotypes were associated with higher clinical risk classification (OR=2.25, p=0.0031) and shorter survival (<5 years) (OR=3.68, p=0.0003), though no correlation was found with immunophenotypic subtypes. No significant associations were identified for rs4789936, rs2009196, or rs7342880. TIMP-2 rs8179090, particularly the CC genotype, may serve as a novel biomarker for childhood ALL susceptibility and prognosis, especially in younger and male patients. Genotyping of this polymorphism could support early risk assessment and personalized clinical management in childhood ALL.