Abstract
PurposeAlthough MYBL2 had been validated to participate in multiple cancers including leukemia, the role of MYBL2 polymorphisms in acute lymphoblastic leukemia (ALL) was still not clear. In this study, we aimed to evaluate the association between MYBL2 single nucleotide polymorphisms (SNPs) and ALL risk in children.MethodsA total of 687 pediatric ALL cases and 971 cancer-free controls from two hospitals in South China were recruited. A case-control study by genotyping three SNPs in the MYBL2 gene (rs285162 C>T, rs285207 A>C, and rs2070235 A>G) was conducted. The associations were assessed by odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Subgroup and stratification analyses were conducted to explore the association of rs285207 with ALL risk in terms of age, sex, immunophenotype, risk level, and other clinical characteristics. The false-positive report probability (FPRP) analysis was performed to verify each significant finding. Functional analysis in silico was used to evaluate the probability that rs285207 might influence the regulation of MYBL2.ResultsOur study demonstrated that rs285207 was related to a decreased ALL risk (adjusted OR = 0.78; 95% CI = 0.63-0.97, P = 0.022) in the dominant model. The associations of rs285207 with ALL risk appeared stronger in patients with pre B ALL (adjusted OR=0.56; 95% CI=0.38-0.84, P=0.004), with normal diploid (adjusted OR=0.73; 95% CI=0.57-0.95, P=0.017), with low risk (adjusted OR=0.68; 95% CI=0.49-0.94, P=0.021), with lower WBC (adjusted OR=0.62; 95% CI=0.43-0.87, P=0.007) or lower platelet level (adjusted OR=0.76; 95% CI=0.59-0.96, P=0.023). With FPRP analysis, the significant association between the rs285207 polymorphism and decreased ALL risk was still noteworthy (FPRP=0.128). Functional analysis showed that IKZF1 bound to DNA motif overlapping rs285207 and had a higher preference for the risk allele A. As for rs285162 C>T and rs2070235 A>G, no significant was found between them and ALL risk.ConclusionIn this study, we revealed that rs285207 polymorphism decreased the ALL risk in children, and rs285207 might alter the binding to IKZF1, which indicated that the MYBL2 gene polymorphism might be a potential biomarker of childhood ALL.
Highlights
Acute lymphoblastic leukemia (ALL) is a malignant proliferation of poorly differentiated lymphocytes, the most common type of pediatric leukemia and the most frequently diagnosed malignancy in children [1, 2]
According to immunophenotype-based classification [35,36,37], 596 (86.75%) cases were diagnosed with B cell ALL (B ALL), including 227 (33.04%) pro B ALL, 200 (29.11%) common B ALL, 166 (24.16%) pre B ALL, and 3 (0.44%) mature B ALL; 61 (8.88%) diagnosed with T cell ALL (T ALL); 30 (4.37%) with no available data (NA)
According to the Single-nucleotide polymorphisms (SNPs) selection strategy, three SNPs that overlapped with transcription factor binding site (TFBS), splicing regulating site (SRS), or non-synonymous SNP were selected (Table 2)
Summary
Acute lymphoblastic leukemia (ALL) is a malignant proliferation of poorly differentiated lymphocytes, the most common type of pediatric leukemia and the most frequently diagnosed malignancy in children [1, 2]. The etiology of ALL is still not well clear, mechanisms involved in it have been extensively investigated. In addition to environmental factors, gene etiology remains the predominant pathogenesis of childhood ALL [3, 4]. Single-nucleotide polymorphisms (SNPs) in cancerassociated key genes (CDKN2A, GATA3, FOXO3, etc.) had been reported to influence ALL risk in children [5,6,7]. Many of the variations in genes influencing ALL remain to be found
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