Abstract for presentation at 11th International Congress of Human Genetics

TP53 R72P and MDM2 SNP309, Disease Expression and Age of Diagnosis of Colorectal Cancer in HNPCC patients

  • Ms Bente Talseth, University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW, Australia
  • Dr Cliff Meldrum, Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia
  • Dr Janina Suchy, International Hereditary Cancer Center, Department of Genetics and Pathology, Szczecin, Poland
  • Dr Grzegroz Kurzawski, International Hereditary Cancer Center, Department of Genetics and Pathology, Szczecin, Poland
  • Dr Jan Lubinski, International Hereditary Cancer Center, Department of Genetics and Pathology, Szczecin, Poland
  • Prof Rodney Scott, University of Newcastle, Hunter Medical Research Institute and Division of Genetics, Hunter Area Pathology Service, NSW, Australia

    • Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer syndrome, which is associated with germline mutations in DNA mismatch repair (MMR) genes. TP53 regulates the transcription of genes necessary for the maintenance of genomic integrity and MDM2 encodes a protein that binds directly to and inhibits TP53. To determine if SNPs in these genes, alone or in combination have any effect on disease expression or age of diagnosis of CRC in HNPCC patients, two different HNPCC populations were investigated.
    Methods: DNA samples from 86 Australian and 134 Polish mutation positive HNPCC patients were genotyped for single nucleotide polymorphisms (SNPs) in TP53 (R72P) and MDM2 (SNP309). The association between the SNPs and disease characteristics; mutation status, disease expression and age of diagnosis of CRC, was tested with Pearson’s Chi-square and Kaplan-Meier survival analysis.
    Results: A difference between Australian and Polish hMLH1 and hMSH2 mutation carriers can be seen for TP53 R72P, this is most likely accounted for by the use of a non-random population (probands and relatives). MDM2 showed a significantly higher frequency of the heterozygote genotype in Polish unaffected MMR gene mutation carriers over the age of 45 years compared to individuals affected with CRC. No significant difference between the age of diagnosis of CRC and genotype of the TP53 R72P or MDM2 SNP309 was observed in Australian or Polish HNPCC patients. The combined analysis of risk of reduced apoptotic ability revealed no significant association between individuals in the different risk groups and disease expression.
    Conclusion: The age of diagnosis of CRC in HNPCC patients is more complex than that predicted by MDM2 SNP309, TP53 R72P or a combination of the two SNPs. It is likely that other modifying factors, both genetic and environmental, play a role in disease expression variance observed in HNPCC.

    Conference Organiser - ICMS Pty Ltd