Molecular Characterization of p53R2 in Head and Neck Ca

头颈钙中 p53R2 的分子表征

• 批准号: 6743247
• 负责人: STUART J WONG
• 金额: $ 18.75万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6743247
• 关键词: DNA damage; DNA repair; clinical research; genetic markers; genetic polymorphism; head /neck neoplasm; human tissue; laser capture microdissection; linkage disequilibriums; neoplasm /cancer radiation therapy; p53 gene /protein; polymerase chain reaction; radiation genetics; ribonucleotide reductase; single nucleotide polymorphism; squamous cell carcinoma; therapy adverse effect

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.

描述（由申请人提供）：放射治疗是局部晚期头颈鳞状细胞癌（HNSCC）患者的主要治疗方式。这些患者的预后通常很差，并且与放射治疗相关的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引起的 DNA 损伤反应的遗传基础可能有助于开发新的 HNSCC 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。最近发现的一个基因，称为 p53R2，在转录上依赖于 p53，似乎在修复辐射引起的 DNA 损伤中发挥重要作用，p53R2 与核糖核苷酸还原酶 (RR) 的 R2 亚基具有显着的同源性，RR 是催化 DNA 合成限速步骤（将核糖核苷酸二磷酸转化为 脱氧核糖核苷酸二磷酸）。 RR 需要为 DNA 合成和 DNA 损伤修复提供核苷酸库。新数据表明，为辐射诱导的 RR 活性提供的是 p53R2，而不是 R2 亚基。 DNA修复。 p53R2 失活被认为会增强细胞对辐射引起的损伤的脆弱性。我们假设，在 HNSCC 中，p53R2 基因的多态性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性预测了肿瘤和正常组织对辐射的不良临床反应。我们将通过检查在放射治疗肿瘤学组 (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。将研究两个具体目标：（1）检查 p53R2 基因的体细胞突变作为 HNSCC 放射治疗的预后肿瘤标志物。我们将鉴定和表征肿瘤细胞中的 p53R2 多态性，并检验 p53R2 基因的体细胞突变会导致不良临床结果的假设，以及 (2) 检查 p53R2 基因的单核苷酸多态性 (SNP) 作为 HNSCC 中正常组织对放射治疗反应的预测标记。我们将鉴定和表征 HNSCC 患者中 p53R2 基因 SNP 的频率，并检验 p53R2 基因 SNP 预测接受放射治疗的 HNSCC 患者中正常组织不良辐射效应的假设。