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Breast Cancer Research and Treatment

, Volume 111, Issue 3, pp 497–504 | Cite as

MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish–Ashkenazi descent

  • Ronit I. Yarden
  • Eitan Friedman
  • Sally Metsuyanim
  • Tsviya Olender
  • Edna Ben-Asher
  • Moshe Zvi PapaEmail author
Epidemiology

Abstract

A functional single nucleotide polymorphism in the promoter of the MDM2 gene, SNP309 (T>G), was recently found to accelerate tumorigenesis in early onset cancer cases. The SNP309 G-allele, introduces an SP1 site in the MDM2 promoter, resulting in enhanced MDM2 expression and activity. Thus, the G-allele of MDM2 SNP309 may represent a cancer predisposing allele. In this report, we assessed the role of SNP309 as a modifier of mutant BRCA1/BRCA2 alleles in inherited breast and ovarian cancer cases among Ashkenazi–Jewish (AJ) women. We genotyped several subsets of AJ women: 138 healthy women, 140 affected BRCA1/2 mutation carriers, 120 asymptomatic BRCA1/2 mutation carriers and 187 sporadic breast cancer patients. The frequency of GG genotype of SNP309 was similar among the different groups. Interestingly, we found almost three times higher frequency of the GG genotype among BRCA1/2 carriers diagnosed with breast and/or ovarian cancer at or under the age of 51 years compared with carriers diagnosed with cancer above the age of 51 years (allele frequency, P = 0.019). The GG genotype was significantly associated with breast and ovarian cancer risk among BRCA1/2 carriers diagnosed before 51 years of age (OR, 3.93; 95% CI, 1.41–10.90, P = 0.009). No significant difference in frequency of the GG genotype was observed between early and late onset non-carrier cancer patients and no association with risk, OR, 1.30; 95% CI 0.69–2.47, P = 0.419). These data suggest that MDM2 SNP309 acts as a modifier of mutant BRCA1/2 mutant alleles in AJ and may accelerate breast and ovarian carcinogenesis in genetically predisposed individuals.

Keywords

MDM2 snp309 BRCA1 BRCA2 Breast and ovarian cancers Cancer risk Jewish–Ashkenazi population 

Notes

Acknowledgement

We thank Drs L.C. Brody, A.J. Levine, and G. Bond for helpful discussions and advice. Grant Support: Funds for Research and Development to the Lab of Genomic Applications and the Department of Surgical Oncology, Sheba Medical Center (R.I.Y and M.Z. Papa).

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Copyright information

© Springer Science+Business Media, LLC. 2007

Authors and Affiliations

  • Ronit I. Yarden
    • 1
    • 2
  • Eitan Friedman
    • 3
  • Sally Metsuyanim
    • 1
  • Tsviya Olender
    • 4
  • Edna Ben-Asher
    • 4
  • Moshe Zvi Papa
    • 1
    • 2
    Email author
  1. 1.Laboratory of Genomic ApplicationsSheba Medical CenterTel-HashomerIsrael
  2. 2.Department of Surgical OncologySheba Medical CenterTel-HashomerIsrael
  3. 3.The Susanne Levy Gertner Oncogenetics UnitThe Danek Gertner Institute of Human Genetics, Sheba Medical CenterTel-HashomerIsrael
  4. 4.The Crown Human Genome Center, Department of Molecular GeneticsThe Weizmann Institute of ScienceRehovotIsrael

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