Germline analysis of thymidine/guanidine polymorphism at position 309 of the Mdm2 promoter in malignant melanoma patients.
p53 is a major tumor suppressor gene, frequently mutated in human cancer, but rarely mutated in malignant melanoma (MM). Mdm2, the major negative regulator of p53, is overexpressed in 50-60% of MM patients, by an unknown mechanism. Single nucleotide polymorphism at position 309 of the Mdm2 promoter correlates with increased Mdm2 levels and reduced p53 activation. We speculated that guanine at position 309 (G309) of the Mdm2 promoter might be a cause of Mdm2 overexpression in MM patients, and associated with increased risk of MM. We aimed to estimate the prevalence of G309 in MM patients. Genomic DNA was collected from a cohort of 28 MM patients of various clinical stages. The relevant DNA stretch was sequenced and thymidine/guanidine polymorphism at position 309 of Mdm2 promoter was examined. We compared the resultant frequencies with the frequencies reported in the literature for the general population. The G allele frequency in the cohort of MM patients was 0.518. This frequency is high compared with the reported frequency of 0.351 in Caucasian healthy populations (odds ratio=1.98, P=0.014). It is also higher than a G allele frequency of 0.464 reported for Ashkenazi Jewish women, although this comparison was not statistically significant (odds ratio=1.14, P=0.76). These results suggest that the single nucleotide polymorphism G309 in the Mdm2 promoter might be an important genetic predisposing factor, and possibly indicate a molecular mechanism of disease regarding MM. These results must be confirmed in a larger cohort of MM patients and controls.
Gluck
Iris
I
Division of Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Simon
Amos J
AJ
Catane
Raphael
R
Pfeffer
Raphael
R
Schachter
Jacob
J
Rechavi
Gideon
G
Bar
Jair
J
D000328:Adult; D000368:Aged; D000375:Aging; D004247:DNA / Q000097:blood; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005854:Germ Cells; D006801:Humans; D007585:Jews / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000208:ethnology / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012727:Sex Characteristics; D012878:Skin Neoplasms / Q000208:ethnology / Q000235:genetics*; D013936:Thymidine / Q000235:genetics
D004247:DNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D013936:Thymidine