Effects of the single nucleotide polymorphism at MDM2 309 on breast cancer patients with/without BRCA1/2 mutations.
BACKGROUND
A germ line single nucleotide polymorphism (SNP) in the first intron of the gene encoding MDM2 at position 309, an important modulator of p53, has been described. BRCA1/2 mutation have been associated with increased rates of breast cancers with mutated P53. It was shown that the presence of MDM2 309 SNP correlated with younger cancer onset age in individuals with a p53 mutations. The differential effects of this SNP were also linked to estrogen receptor activation. Here we report on our study of 453 Ashkenazi breast cancer patients of whom 180 were positive for the known Ashkenazi BRCA1/2 mutations


METHODS
DNA from breast cancer patients was obtained for analysis of one of the three common BRCA1/2 mutations and MDM2 SNP309. Data regarding cancer onset and death ages was obtained from our database and Statistical analysis was performed using the SPSS statistical package (SPCC Inc., Chicago, IL), and JMP software (SAS Institute, Cary, NC).


RESULTS
The percentage of MDM2 SNP309 in control and BRCA 1/2 population which is similar to that reported for other Jewish Ashkenazi populations at 52.2% for the heterozygotes and 25.0% for MDM2SNP309G/G and 22.8% for MDM2SNP309T/T.There was not a statistical significant difference in median age of disease onset in the different MDM2 SNP309 subgroups of the BRCA1/2 carriers. When we further divided the group into under and above 51 years old ( presumed menopause age) in the BRCA1 positive subset we found that there were less patients of the MDM2SNP309 G/G versus the MDM2SNP309 T/T in the over 51 patient group (p = 0.049). This result has been obtained in a relatively small subgroup and is of borderline statistical significance. Interestingly, in the BRCA1/2 mutation carriers, we found a survival advantage for patients harboring the SNP309 G/G genotype (p = 0.0086) but not for the 272 patients not harbouring this mutations.


CONCLUSIONS
MDM2SNP309G/G main effect on BRCA1/2 positive mutation carriers is linked to its effect on patients survival. Further research is needed in order to understand the reason for this difference.
Nechushtan
Hovav
H
Department of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. hovavnech@hadassah.org.il
Hamburger
Tamar
T
Mendelson
Susan
S
Kadouri
Luna
L
Sharon
Nir
N
Pikarsky
Eli
E
Peretz
Tamar
T
D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007585:Jews / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016019:Survival Analysis
D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2