MDM2 SNP309 genotype influences survival of metastatic but not of localized neuroblastoma.
BACKGROUND
MDM2 is a major negative regulator of p53 function and is directly regulated by MYCN in neuroblastoma (NB) cells. MDM2 SNP309, a T-to-G substitution in the MDM2 promoter associated with higher gene expression compared to wild-type, may attenuate the p53 pathway in NB, in which p53 mutations are rare. We investigated its impact on NB development and survival in relation with major clinical and biological characteristics.


METHODS
A consecutive cohort of 497 NB children, diagnosed in Italy between 1995 and 2005, and a healthy control population of 471 adults were genotyped for MDM2 SNP309. NB patients were followed up until June 30, 2008.


RESULTS
Patients and controls showed similar distribution of MDM2 SNP309 genotypes. In patients, the polymorphism was not associated with any characteristic at diagnosis. In localized stages no effect of the polymorphism on survival was evident. In stage 4 patients overall survival (OS), event free survival (EFS) and survival after relapse (SAR) were significantly poorer for TG/GG than for TT patients (P = 0.008; P = 0.013; P = 0.046, respectively). In this group, such an effect was more evident in patients with MYCN amplification (OS: P < 0.001; EFS: P = 0.028; SAR: P < 0.001).


CONCLUSIONS
While MDM2 SNP309 status does not affect the risk of developing NB nor disease outcome for localized cancer cases, it significantly correlates with survival in stage 4 NB patients, particularly in the presence of MYCN amplification. The impact of small molecule inhibitors of MDM2 activity in the management of such patients could be usefully considered.
Perfumo
Chiara
C
Molecular Mutagenesis and DNA Repair Unit, National Cancer Research Institute, Genoa, Italy. chiara.perfumo@istge.it
Parodi
Stefano
S
Mazzocco
Katia
K
Defferrari
Raffaella
R
Inga
Alberto
A
Scarrà
Giovanna Bianchi
GB
Ghiorzo
Paola
P
Haupt
Riccardo
R
Tonini
Gian Paolo
GP
Fronza
Gilberto
G
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D016158:Genes, p53; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009362:Neoplasm Metastasis; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2