Radiation therapy is a primary treatment modality for patients with locally advanced head and neck squamous cell cancer (HNSCC). The prognosis of these patients is generally poor and the frequency and severity of treatment related side effects from radiation are unacceptably high. Efforts to understand the genetic basis of tumor and normal tissue response to radiation-induced DNA damage may help develop new treatment strategies for HNSCC. Efforts are underway to discover candidate genes that predict tumor or normal tissue response to radiation. A recently identified gene, called p53R2, is transcriptionally dependent upon p53 and appears to play an important role in repair of radiation-induced DNA damage, p53R2 displays significant homology to the R2 subunit of ribonucleotide reductase (RR) - the enzyme that catalyzes the rate limiting step of DNA synthesis (conversion of ribonucleotide diphosphates to deoxyribonucleotide diphosphates). RR is required to supply nucleotide pools for DNA synthesis and for repair of DNA damage. New data suggests that it is p53R2, rather than the R2 subunit, that provides the RR activity for radiation-induced DNA repair. Inactivation of p53R2 is thought to enhance the vulnerability of cells to radiation-induced damage. We hypothesize that in HNSCC, polymorphisms of the p53R2 gene alter the functional capacity of cells to repair radiation-induced DNA damage, and that specific mutations or polymorphisms of the gene predict adverse clinical response of tumor and normal tissue to radiation. We will test this hypothesis by examining a tissue bank of stage III and IV HNSCC patients treated in Radiation Therapy Oncology Group (RTOG) Trial 90-03.
Two specific aims will be examined: (1) To examine somatic mutations of the p53R2 gene as a prognostic tumor marker of radiation therapy in HNSCC. We will identify and characterize p53R2 polymorphisms in tumor cells, and test the hypothesis that somatic mutations of the p53R2 gene confer adverse clinical outcome, and (2) To examine single nucleotide polymorphisms (SNPs) of the p53R2 gene as predictive markers of normal tissue response to radiation therapy in HNSCC. We will identify and characterize the frequency of p53R2 gene SNPs in HNSCC patients and test the hypothesis that p53R2 gene SNPs predict adverse normal tissue radiation effects in HNSCC patients treated with radiation.
