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Published on: June 21, 2018
A Greek Case-Control Replication Study of IKZF1 rs4132601 and CDKN2A rs3731217 in Childhood Acute Lymphoblastic
Ioannis Kyriakidis1, Spyridoula D Katsarou1,2, Maria I Zervou3
1Department of Pediatric Hematology-Oncology and Autologous Hematopoietic Stem Cell Transplantation Unit, University Hospital of Heraklion and Laboratory of Blood Diseases and Childhood Cancer Biology, School of Medicine, University of Crete, 71003 Heraklion, Greece.
Background/Objectives:
Inherited variants in IKZF1 and CDKN2A/2B are among the most consistently reported germline susceptibility markers for childhood acute lymphoblastic leukemia (ALL). Nonetheless, effect sizes differ across ancestry groups, age ranges, and immunophenotypic subtypes, making well-characterized population-specific replication studies valuable for refining ancestry-specific evidence. This study examined two sentinel variants with historical relevance, IKZF1 rs4132601 and CDKN2A rs3731217, within a pediatric Greek cohort.
Methods:
A case-control study with retrospective case ascertainment and control recruitment through routine pediatric visits was conducted, comprising 50 children and adolescents with ALL and 91 healthy controls from Crete, Greece. Constitutional DNA was isolated from peripheral blood samples collected during remission in cases, while controls provided peripheral blood for targeted germline genotyping. Genotyping was performed using PCR-restriction fragment length polymorphism analysis. We evaluated Hardy-Weinberg equilibrium and genotype and allele distributions and analyzed the data using logistic regression models.
Results:
Control minor allele frequencies were broadly compatible with public European reference data. Neither IKZF1 rs4132601 nor CDKN2A rs3731217 showed a significant association with susceptibility to childhood ALL under either genotype-based or additive models. Results remained consistent after excluding T-cell ALL cases. Exploratory genotype-phenotype analyses did not reveal robust associations with clinical or molecular features.
Conclusions:
In this first Greek pediatric assessment of IKZF1 rs4132601 and CDKN2A rs3731217, no significant association with ALL susceptibility was observed. Within the constraints of limited statistical power, these negative findings provide population-specific evidence, refine regional allele-frequency and effect-size estimates, highlight the limitations of relying on single historical sentinel single-nucleotide polymorphisms (SNPs), and support future ancestry-informed and polygenic approaches in southeastern European cohorts.
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