Molecular Characterization of p53R2 in Cancer

描述(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。这些患者的预后普遍较差，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。努力了解肿瘤的遗传基础和正常组织对辐射诱导的DNA损伤的反应可能有助于开发新的HNSCC治疗策略。目前正在努力寻找预测肿瘤或正常组织对辐射反应的候选基因。最近发现的一个基因p53R2在转录上依赖于p53，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亚基显示出显著的同源性，RR是催化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)的酶。RR是为DNA合成和DNA损伤修复提供核苷酸池所必需的。新的数据表明，为辐射诱导的RR活性提供的是p53R2，而不是R2亚基 DNA修复。P53R2的失活被认为增加了细胞对辐射损伤的脆弱性。我们假设在HNSCC中，p53R2基因的多态改变了细胞修复辐射引起的DNA损伤的功能能力，并且该基因的特定突变或多态预测了肿瘤和正常组织对辐射的不良临床反应。我们将通过检查放射治疗肿瘤组(RTOG)试验90-03中接受治疗的III期和IV期HNSCC患者的组织库来检验这一假设。我们将研究两个特定的目标：(1)检测p53R2基因的体细胞突变作为HNSCC放射治疗预后的肿瘤标志物。我们将鉴定和鉴定肿瘤细胞中的p53R2多态，并验证p53R2基因的体细胞突变会导致不良临床结局的假设，以及(2)检测p53R2基因的单核苷酸多态(SNPs)作为预测HNSCC中正常组织对放射治疗的反应的标志物。我们将鉴定和鉴定p53R2基因SNPs在HNSCC患者中的频率，并验证p53R2基因SNPs预测HNSCC患者接受放射治疗的不良正常组织辐射效应的假设。

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.