Molecular Characterization of p53R2 in Head and Neck Ca

描述（由申请人提供）：放射治疗是局部晚期头颈部鳞状细胞癌（HNSCC）患者的主要治疗方式。这些患者的预后通常很差，放射治疗相关副作用的频率和严重程度高得令人无法接受。努力了解肿瘤和正常组织对辐射诱导的DNA损伤反应的遗传基础可能有助于制定新的治疗策略。人们正在努力发现预测肿瘤或正常组织对辐射反应的候选基因。最近发现的基因p53R2在转录上依赖于p53，似乎在辐射诱导的DNA损伤修复中发挥重要作用，p53R2与核糖核苷酸还原酶（RR）的R2亚基具有显著的同源性，rna核苷酸还原酶催化DNA合成的限速步骤（将核糖核苷酸二磷酸转化为脱氧核糖核苷酸二磷酸）。需要RR为DNA合成和修复DNA损伤提供核苷酸池。新的数据表明，是p53R2，而不是R2亚基，提供辐射诱导的RR活性

DESCRIPTION (provided by applicant): 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.