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

  • Epidemiology
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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.

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References

  1. Foulkes WD (2006) BRCA1 and BRCA2: chemosensitivity, treatment outcomes and prognosis. Fam Cancer 5(2):135–142

    Article  PubMed  CAS  Google Scholar 

  2. King MC, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302(5645):643–646

    Article  PubMed  CAS  Google Scholar 

  3. Narod SA, Foulkes WD (2004) BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4(9):665–676

    Article  PubMed  CAS  Google Scholar 

  4. Jakubowska A et al (2007) The RAD51 135 G>C polymorphism modifies breast cancer and ovarian cancer risk in Polish BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev 16(2):270–275

    Article  PubMed  CAS  Google Scholar 

  5. Levy-Lahad E et al (2001) A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci USA 98(6):3232–3236

    Article  PubMed  CAS  Google Scholar 

  6. Wang WW et al (2001) A single nucleotide polymorphism in the 5′ untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10(9):955–960

    PubMed  CAS  Google Scholar 

  7. Kadouri L et al (2004) Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers. Int J Cancer 108(3):399–403

    Article  PubMed  CAS  Google Scholar 

  8. Rebbeck TR et al (2001) Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history. Cancer Res 61(14):5420–5424

    PubMed  CAS  Google Scholar 

  9. Vidarsdottir L et al (2007) Breast cancer risk associated with AURKA 91T –>A polymorphism in relation to BRCA mutations. Cancer Lett 250(2):206–212

    Article  PubMed  CAS  Google Scholar 

  10. Couch FJ et al (2007) AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 Study. Cancer Epidemiol Biomarkers Prev 16(7):1416–1421

    Article  PubMed  CAS  Google Scholar 

  11. Yarden RI, Papa MZ (2006) BRCA1 at the crossroad of multiple cellular pathways: approaches for therapeutic interventions. Mol Cancer Ther 5(6):1396–1404

    Article  PubMed  CAS  Google Scholar 

  12. Moynahan ME (2002) The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans. Oncogene 21(58):8994–9007

    Article  PubMed  CAS  Google Scholar 

  13. Brugarolas J, Jacks T (1997) Double indemnity: p53, BRCA and cancer. p53 mutation partially rescues developmental arrest in Brca1 and Brca2 null mice, suggesting a role for familial breast cancer genes in DNA damage repair. Nat Med 3(7):721–722

    Article  PubMed  CAS  Google Scholar 

  14. Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8(4):275–283

    Article  PubMed  CAS  Google Scholar 

  15. Phillips KA et al (1999) Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carriers of BRCA1 mutations. J Natl Cancer Inst 91(5):469–473

    Article  PubMed  CAS  Google Scholar 

  16. Gasco M, Yulug IG, Crook T (2003) TP53 mutations in familial breast cancer: functional aspects. Hum Mutat 21(3):301–306

    Article  PubMed  CAS  Google Scholar 

  17. Xu X et al (2001) Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet 28(3):266–271

    Article  PubMed  CAS  Google Scholar 

  18. Haupt Y (2004) p53 Regulation: a family affair. Cell Cycle 3(7):884–885

    PubMed  CAS  Google Scholar 

  19. Bond GL et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119(5):591–602

    Article  PubMed  CAS  Google Scholar 

  20. Dharel N et al (2006) MDM2 promoter SNP309 is associated with the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Clin Cancer Res 12(16):4867–4871

    Article  PubMed  CAS  Google Scholar 

  21. Bond GL et al (2006) MDM2 SNP309 accelerates colorectal tumour formation in women. J Med Genet 43(12):950–952

    Article  PubMed  CAS  Google Scholar 

  22. Bond GL, Levine AJ (2007) A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans. Oncogene 26(9):1317–1323

    Article  PubMed  CAS  Google Scholar 

  23. Hirata H et al (2007) MDM2 SNP309 polymorphism as risk factor for susceptibility and poor prognosis in renal cell carcinoma. Clin Cancer Res 13(14):4123–4129

    Article  PubMed  CAS  Google Scholar 

  24. Petenkaya A et al (2006) Lack of association between the MDM2-SNP309 polymorphism and breast cancer risk. Anticancer Res 26(6C):4975–4977

    PubMed  CAS  Google Scholar 

  25. Copson ER et al (2006) Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers. BMC Cancer 6:80

    Article  PubMed  Google Scholar 

  26. Bond GL et al (2006) MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66(10):5104–5110

    Article  PubMed  CAS  Google Scholar 

  27. Wasielewski M et al (2007) MDM2 SNP309 accelerates familial breast carcinogenesis independently of estrogen signaling. Breast Cancer Res Treat 104(2):153–157

    Article  PubMed  CAS  Google Scholar 

  28. Bar-Sade RB et al (1998) The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim. Hum Mol Genet 7(5):801–805

    Article  PubMed  CAS  Google Scholar 

  29. Bar-Sade RB et al (1997) Could the 185delAG BRCA1 mutation be an ancient Jewish mutation? Eur J Hum Genet 5(6):413–416

    PubMed  CAS  Google Scholar 

  30. Neuhausen SL et al (1998) Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. Am J Hum Genet 62(6):1381–1388

    Article  PubMed  CAS  Google Scholar 

  31. Atwal GS et al (2007) Haplotype structure and selection of the MDM2 oncogene in humans. Proc Natl Acad Sci USA 104(11):4524–4529

    Article  PubMed  CAS  Google Scholar 

  32. Phelan CM et al (1996) Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. Nat Genet 12(3):309–311

    Article  PubMed  CAS  Google Scholar 

  33. Kadouri L et al (2004) A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers. Br J Cancer 90(10):2002–2005

    Article  PubMed  CAS  Google Scholar 

  34. Foulkes WD et al (2004) Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin Cancer Res 10(6):2029–2034

    Article  PubMed  CAS  Google Scholar 

  35. Jasin M (2002) Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene 21(58):8981–8993

    Article  PubMed  CAS  Google Scholar 

  36. Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108(2):171–182

    Article  PubMed  CAS  Google Scholar 

  37. Wilkening S et al (2007) No association between MDM2 SNP309 promoter polymorphism and basal cell carcinoma of the skin. Br J Dermatol 157(2):375–377

    Article  PubMed  CAS  Google Scholar 

  38. Campbell IG, Eccles DM, Choong DY (2006) No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer. Cancer Lett 240(2):195–197

    Article  PubMed  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Laboratory of Genomic Applications, Sheba Medical Center, Tel-Hashomer, 52621, Israel

    Ronit I. Yarden, Sally Metsuyanim & Moshe Zvi Papa

  2. Department of Surgical Oncology, Sheba Medical Center, Tel-Hashomer, 52621, Israel

    Ronit I. Yarden & Moshe Zvi Papa

  3. The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel

    Eitan Friedman

  4. The Crown Human Genome Center, Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel

    Tsviya Olender & Edna Ben-Asher

Authors
  1. Ronit I. Yarden
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  2. Eitan Friedman
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  3. Sally Metsuyanim
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  4. Tsviya Olender
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  5. Edna Ben-Asher
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  6. Moshe Zvi Papa
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Correspondence to Moshe Zvi Papa.

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Yarden, R.I., Friedman, E., Metsuyanim, S. et al. MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish–Ashkenazi descent. Breast Cancer Res Treat 111, 497–504 (2008). https://doi.org/10.1007/s10549-007-9797-z

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  • DOI: https://doi.org/10.1007/s10549-007-9797-z

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