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Effects of the single nucleotide polymorphism at MDM2 309 on breast cancer patients with/without BRCA1/2 mutations.

Nechushtan H, Hamburger T, Mendelson S, Kadouri L, Sharon N, Pikarsky E, Peretz T - BMC Cancer (2009)

Bottom Line: 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.MDM2SNP309G/G main effect on BRCA1/2 positive mutation carriers is linked to its effect on patients survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. hovavnech@hadassah.org.il

ABSTRACT

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.

Conclusion: 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.

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Related in: MedlinePlus

Survival analysis of BRCA1/2 mutation carriers (A) and non carriers (B) according to their MDM2 SNP type. SNP309 G/G carriers were compared to the combined group of SNP309 G/T and SNP309 T/T. In the BRCA carrier group there were 41 G/G patients of whom 7 died (median survival 412 months) while in the combined SNP309 G/T and T/T group there were 126 patients of whom 35 died (median survival 301 months). According to a log-rank test the significance of the difference in survival was P = 0.0086. In the control group the survival for the MDM2 SNP309 G/G carriers was was not statistically different (p = 0.8).
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Figure 2: Survival analysis of BRCA1/2 mutation carriers (A) and non carriers (B) according to their MDM2 SNP type. SNP309 G/G carriers were compared to the combined group of SNP309 G/T and SNP309 T/T. In the BRCA carrier group there were 41 G/G patients of whom 7 died (median survival 412 months) while in the combined SNP309 G/T and T/T group there were 126 patients of whom 35 died (median survival 301 months). According to a log-rank test the significance of the difference in survival was P = 0.0086. In the control group the survival for the MDM2 SNP309 G/G carriers was was not statistically different (p = 0.8).

Mentions: Our next step was to study the survival of the different subpopulations according to the three different genotypes (T/T, G/G or G/T at the -309 position of the MDM2 gene). There was a distinct survival advantage in the BRCA1/2 mutation carrier group for the patients homozygous for G/G at the -309 position, compared to the patients harboring the SNP309 G/T or T/T (Fig 2a p = 0.0086 log rank test, median survival 290 versus 412 months). This advantage was not found in the non BRCA1/2 carriers (Fig. 2b). Cox multivariate analysis did not reveal modification of the MDM2 SNP309 effect on survival due to cancer onset age.


Effects of the single nucleotide polymorphism at MDM2 309 on breast cancer patients with/without BRCA1/2 mutations.

Nechushtan H, Hamburger T, Mendelson S, Kadouri L, Sharon N, Pikarsky E, Peretz T - BMC Cancer (2009)

Survival analysis of BRCA1/2 mutation carriers (A) and non carriers (B) according to their MDM2 SNP type. SNP309 G/G carriers were compared to the combined group of SNP309 G/T and SNP309 T/T. In the BRCA carrier group there were 41 G/G patients of whom 7 died (median survival 412 months) while in the combined SNP309 G/T and T/T group there were 126 patients of whom 35 died (median survival 301 months). According to a log-rank test the significance of the difference in survival was P = 0.0086. In the control group the survival for the MDM2 SNP309 G/G carriers was was not statistically different (p = 0.8).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2667534&req=5

Figure 2: Survival analysis of BRCA1/2 mutation carriers (A) and non carriers (B) according to their MDM2 SNP type. SNP309 G/G carriers were compared to the combined group of SNP309 G/T and SNP309 T/T. In the BRCA carrier group there were 41 G/G patients of whom 7 died (median survival 412 months) while in the combined SNP309 G/T and T/T group there were 126 patients of whom 35 died (median survival 301 months). According to a log-rank test the significance of the difference in survival was P = 0.0086. In the control group the survival for the MDM2 SNP309 G/G carriers was was not statistically different (p = 0.8).
Mentions: Our next step was to study the survival of the different subpopulations according to the three different genotypes (T/T, G/G or G/T at the -309 position of the MDM2 gene). There was a distinct survival advantage in the BRCA1/2 mutation carrier group for the patients homozygous for G/G at the -309 position, compared to the patients harboring the SNP309 G/T or T/T (Fig 2a p = 0.0086 log rank test, median survival 290 versus 412 months). This advantage was not found in the non BRCA1/2 carriers (Fig. 2b). Cox multivariate analysis did not reveal modification of the MDM2 SNP309 effect on survival due to cancer onset age.

Bottom Line: 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.MDM2SNP309G/G main effect on BRCA1/2 positive mutation carriers is linked to its effect on patients survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. hovavnech@hadassah.org.il

ABSTRACT

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus