MDM2 polymorphism increases susceptibility to childhood acute myeloid leukemia: a report from the Children's Oncology Group
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Published on: October 3, 2018
Christine L Phillips1, Robert Gerbing, Todd Alonzo
1Division of Hematology Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. christine.phillips@cchmc.org
Background:
The variant polymorphism in the gene MDM2, SNP309, leads to increased level of mdm2 protein and subsequent downregulation of p53 tumor suppressor pathway. Presence of this single nucleotide polymorphism (SNP) has been associated with earlier tumorigenesis in patients with Li-Fraumeni syndrome, as well as decreased survival in patients with CLL. In addition, cells homozygous (G/G) for SNP 309 were found to have 10-fold increase resistance to topoisomerase II inhibitors in vitro.
Procedure:
We genotyped children (n = 575) with de novo acute myeloid leukemia (AML) treated on three Children's Oncology Group protocols (CCG 2941/2961/AAML 03P1) for the presence of SNP309. Healthy blood donors were genotyped as control population.
Results:
The variant G/G genotype was associated with an increased susceptibility to AML (OR 1.5; P = 0.049). However, the presence of the variant allele at SNP309 did not modify disease response or toxicity in children treated on CCG protocols 2941/2961.
Conclusions:
The variant SNP 309 influences susceptibility to pediatric AML, but does not impact overall response to therapy.
Insights
The MDM2 SNP309 variant increases susceptibility to pediatric acute myeloid leukemia (AML). However, this genetic marker does not affect treatment response or toxicity in children with AML.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The MDM2 gene variant, SNP309, affects the p53 tumor suppressor pathway.
- SNP309 is linked to earlier cancer development and reduced survival in certain conditions.
- Cells with the SNP309 G/G genotype show increased resistance to topoisomerase II inhibitors.
Purpose of the Study:
- To investigate the association between MDM2 SNP309 and susceptibility to pediatric acute myeloid leukemia (AML).
- To determine if SNP309 influences treatment response and toxicity in children with AML.
Main Methods:
- Genotyping of 575 children with de novo AML.
- Comparison of SNP309 genotypes in AML patients and healthy blood donors.
- Analysis of treatment response and toxicity in children on specific oncology protocols.
Main Results:
- The SNP309 G/G genotype was associated with increased susceptibility to AML (OR 1.5; P = 0.049).
- No significant impact of the SNP309 variant allele on disease response was observed.
- The variant did not modify toxicity in children undergoing treatment.
Conclusions:
- The MDM2 SNP309 variant plays a role in susceptibility to pediatric AML.
- SNP309 does not appear to influence the overall response to therapy in pediatric AML patients.
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