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MDM2 promoter SNP285 and SNP309; phylogeny and impact on cancer risk

Stian Knappskog1, Per E Lønning

  • 1Section of Oncology, Institute of Medicine, University of Bergen, 5020 Bergen, Norway. Stian.Knappskog@med.uib.no

Oncotarget
|March 26, 2011
PubMed

Insights

The MDM2 gene

Area of Science:

  • Molecular biology and cancer genetics.
  • Focuses on gene regulation and its impact on cancer risk.

Background:

  • MDM2 protein regulates cell growth, senescence, and apoptosis by inhibiting p53 and RB proteins.
  • MDM2 amplification or overexpression is common in solid tumors.
  • MDM2 promoter polymorphism (SNP309T>G) affects Sp1 transcription factor binding and MDM2 expression.

Purpose of the Study:

  • To investigate the functional impact of a newly identified MDM2 promoter polymorphism (SNP285G>C) on Sp1 binding and cancer risk.
  • To evaluate the combined effect of SNP285G>C and SNP309T>G on breast and ovarian cancer risk.

Main Methods:

  • Surface plasmon resonance technology was used to assess Sp1 transcription factor binding to the MDM2 promoter.
  • Genotyping of SNP309T>G and SNP285G>C polymorphisms in patient cohorts.
  • Statistical analysis to determine the association between genotypes/haplotypes and cancer risk.

Main Results:

  • SNP309G enhanced Sp1 binding by 22%, while SNP285C reduced Sp1 binding by 51%.
  • The 285C/309G haplotype, present in ~12% of European populations, was associated with reduced breast cancer risk (21%) and ovarian cancer risk (26%).
  • A significant reduction in ovarian cancer risk (37%) was observed in 309TG heterozygotes carrying the 285C allele.

Conclusions:

  • The MDM2 SNP285C polymorphism significantly modulates Sp1 binding and reduces breast and ovarian cancer risk, particularly in combination with SNP309G.
  • The 285C/309G haplotype appears to be a relatively young polymorphism, with lower frequency in Asian populations.
  • These findings highlight the complex interplay between genetic variations in the MDM2 promoter and cancer susceptibility.

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