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MDM2 as a modifier gene in retinoblastoma

Laurent Castéra1, Audrey Sabbagh, Catherine Dehainault

  • 1Pharm D, Department of Oncogenetics, Institut Curie, Paris, France.

Journal of the National Cancer Institute
|November 6, 2010
PubMed

Insights

A specific gene variant in MDM2 (a gene that affects p53 and pRB pathways) is linked to retinoblastoma development. This finding identifies MDM2 as the first modifier gene for retinoblastoma.

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Retinoblastoma exhibits variable onset age and tumor number, suggesting genetic modifiers.
  • The pRB and p53 pathways are crucial in retinoblastoma development.
  • MDM2 influences p53 and pRB protein levels, making it a candidate for genetic modification.

Purpose of the Study:

  • To investigate the role of the MDM2 gene promoter polymorphism (rs2279744, 309T>G) as a genetic modifier in retinoblastoma.
  • To determine if the MDM2 309G allele is associated with disease phenotype and age of onset in retinoblastoma families.

Main Methods:

  • Genetic transmission analysis was performed in 326 individuals from 70 retinoblastoma families.
  • Genotyping for the MDM2 309T>G single-nucleotide polymorphism (SNP rs2279744) was conducted.
  • Association analyses (family-based and transmission disequilibrium) were used to link genotype to retinoblastoma incidence and phenotype.

Main Results:

  • The MDM2 309G allele showed a statistically significant association with retinoblastoma incidence (bilateral or unilateral) in family-based analyses (P = .001).
  • A recessive genetic model indicated that affected individuals were more likely to be homozygous for the G allele.
  • Transmission disequilibrium analysis corroborated the association, with an odds ratio of 4.0 (95% CI, 1.3–12.0).

Conclusions:

  • MDM2 is identified as the first genetic modifier gene for retinoblastoma.
  • The MDM2 309G genotype is strongly associated with retinoblastoma development.
  • Enhanced MDM2 expression may promote tumor formation by increasing pRB haploinsufficiency or inhibiting p53-mediated apoptosis.

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