Abstract for presentation at 11th International Congress of Human Genetics

Are polymorphisms in the toll-like receptors associated with disease risk in HNPCC?

  • Miss Katie Ashton, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia
  • Dr Cliff Meldrum, Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, Australia
  • Ms Mary McPhillips, Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, 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, Hunter Area Pathology Service, University of Newcastle, Hunter Medical Research Institute, Newcastle, Australia

    • Purpose: Toll-like receptors (TLRs) are vital for the activation and maintenance of the innate immune system through recognising and responding to pathogen-associated molecular patterns of a diverse range of pathogens. Defects in TLRs have been implicated in inflammation and evidence suggests that they are involved in the initiation and development of human cancers. To determine whether there is a role for inflammation in the development of malignancy in HNPCC, we studied four single nucleotide polymorphisms (SNPs) in three TLR genes; TLR2, TLR4 and TLR9. HNPCC is a familial predisposition to epithelial malignancies, most notably colorectal (CRC) and endometrial (EC) cancers.
    Methods: All participants in the study harboured a mutation in hMLH1 or hMSH2. Two populations were studied: Australian (n=89), Polish (n=134). Using Real Time PCR, 4 SNPs in 3 genes (TLR2 G2408A, TLR4 A12874G, TLR9-1237T>C and TLR9-1486T>C) were examined and their association with disease expression in HNPCC was determined by Pearson’s Chi-squared and Kaplan-Meier Survival analysis.
    Results: In the Australian population, the TLR9-1237C allele was significantly associated with decreased cancer risk. Patients unaffected with CRC had a higher frequency of the mutant genotypes (p=0.01). In the Polish population, the patients affected with EC had a higher frequency of the mutant alleles for both TLR2 G2408A and TLR9-1237 compared to those without EC (p=0.02 and p=0.03 respectively). In addition, Polish patients that harboured a hMSH2 mutation had a higher frequency of the TLR2 mutant allele than those that had a mutation in hMLH1 (p=0.001), indicating variation between patients with different mismatch repair mutations.
    Conclusions: These results suggest that SNPs in TLRs are associated with a dysfunction in the pro- and anti-inflammatory response. This study indicates that the immune system plays a role in altering the risk of malignancy in patients predisposed to develop disease.

    Conference Organiser - ICMS Pty Ltd