MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia.
OBJECTIVE
A single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2 leading to increased expression of MDM2 and attenuated function of p53 has been negatively associated with onset and outcome of disease in solid tumors. Because inactivation of p53 by deletion and/or mutations also impacts on the clinical course of B-cell chronic lymphocytic leukemia (B-CLL), we assessed the role of the SNP309 genotype in B-CLL.


METHODS
The frequency of SNP309 T/T, T/G, or G/G genotypes and the p53 status (wild type, mutated, or deleted) were assessed and correlated with clinical outcome in 140 B-CLL patients and a second independent cohort. In addition, the correlation of the MDM2 SNP309 genotype with the MDM2 protein expression level in B-CLL cells was evaluated by immunoblotting.


RESULTS
A significant negative association of the SNP309 T/G and G/G genotypes with overall survival was seen (T/G genotype, relative risk = 3.7; 95% CI, 1.2 to 11.5; P = .02; G/G genotype, relative risk = 9.1; 95% CI, 2.4 to 35.1; P = .001), but no correlation with incidence or onset of B-CLL was observed. The influence of the heterozygous SNP309 T/G genotype on treatment-free survival depended on the p53 status but not on the CD38, Zap-70, or IgVH mutational status or Rai stage of B-CLL patients. The unfavorable SNP309 T/G and G/G genotypes were associated with a gene-dosage-dependent increase of MDM2 expression.


CONCLUSIONS
The MDM2 SNP309 genotype influencing MDM2 expression levels was identified as an additional independent risk factor in B-CLL. Targeting MDM2-p53 interactions might emerge as a successful treatment strategy for B-CLL.
Gryshchenko
Irina
I
Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Salzburg University Hospital, Muellner Hauptstrasse 48, A-5020 Salzburg, Austria.
Hofbauer
Sebastian
S
Stoecher
Markus
M
Daniel
Peter T
PT
Steurer
Michael
M
Gaiger
Alexander
A
Eigenberger
Karin
K
Greil
Richard
R
Tinhofer
Inge
I
D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis / Q000235:genetics
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051746:ZAP-70 Protein-Tyrosine Kinase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1