MDM2 polymorphism increases susceptibility to childhood acute myeloid leukemia: a report from the Children's Oncology Group.
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.


METHODS
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.
Phillips
Christine L
CL
Division of Hematology Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. christine.phillips@cchmc.org
Gerbing
Robert
R
Alonzo
Todd
T
Perentesis
John P
JP
Harley
Isaac T W
IT
Meshinchi
Soheil
S
Bhatla
Deepika
D
Radloff
Gretchen
G
Davies
Stella M
SM
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2