P53 GENE ALTERATIONS IN X-RAYED TINEA CAPITIS PATIENTS

X 射线检查的头癣患者中的 P53 基因改变

• 批准号: 2112204
• 负责人: FREDRIC Jay Burns
• 金额: $ 26.83万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2112204
• 关键词: DNA; DNA damage; X ray; cancer risk; chemical fingerprinting; chromosome translocation; gene deletion mutation; human genetic material tag; human subject; neoplasm /cancer epidemiology; neoplasm /cancer genetics; nucleic acid sequence; polymerase chain reaction; prognosis; radiation related neoplasm /cancer; single strand conformation polymorphism; skin neoplasms; southern blotting; tinea; tumor suppressor genes

The ongoing epidemiological study of about 2000 x-radiated tinea capitis patients and 1400 controls is providing evidence that x-irradiation in childhood causes a significant increase (relative risk = 3.7 for single tumors and = 8.0 for multiple tumors) in the incidence of basal cell carcinomas (BCCs). Other evidence suggests Uv light also plays a role, possibly as a promoter of x-ray initiated tumors, although Uv may also act as an tumor initiator by producing DNA damage in the form of CC to TT or C to T base changes. Some patients in the tinea study exhibit evidence of substantially higher than normal risk of a skin cancers. The heightened risk is apparent in patients who have already developed a cancer; the risk of a second cancer is roughly 40% per 5 years versus only about 2% per 5 years for those without a prior cancer. A preliminary study of skin tumors from the x-irradiated patients showed evidence of possible x-ray damage to the p53 gene; 5 of 6 BCCs or epitheliomas exhibited deletion or translocation damage to exons 7, 8 or 9, and 1 of 6 patients showed a total p53 deletion in DNA from blood leukocytes. The research proposed here is designed to answer the following questions raised by the initial findings in this unique patient population: 1. How closely are the genetic changes in the p53 gene of the induced cancers linked to the probable etiologic agent (UV or x-ray), 2. are p53 gene alterations as measured in blood leukocytes of high cancer risk patients a possible genetic basis for their increased susceptibility, and 3. are multiple skin cancers on the same patient derived from distinct and independent genetic lesions. Skin cancers presenting in the clinic will be removed and examined histologically. Tumor DNA will be extracted and analyzed by polymerase chain reaction (PCR) as a way to quantity major internal deletions and other rearrangements, while SSCP followed by DNA sequencing will be used to identify base pair alterations. DNA fingerprinting techniques will be used to establish whether multiple cancers on the same patient are genetically distinct. Specific exon probes will be utilized to on Southern blots to distinguish small deletions from translocations. The proposed work will establish the types and incidence of p53 gene alterations in radiation-induced skin BCCs and whether the type of p53 alteration is predictive of the response to secondary prevention by topical 5-fluorouracil.

正在进行的约2000例X-射线照射的头癣流行病学研究 患者和1400名对照人员正在提供证据表明，在 童年导致显著增加(单身的相对风险=3.7 肿瘤和多发性肿瘤=8.0)在基底细胞发病率中 癌症(BCC)。其他证据表明，紫外线也起到了一定作用， 可能是x射线引发的肿瘤的促进剂，尽管紫外线也可能 通过以CC-TO的形式产生DNA损伤而起到肿瘤启动剂的作用 TT或C到T碱基发生变化。癣研究中的一些患者展示了 患皮肤癌的风险大大高于正常水平的证据。这个 风险增加在已经患上 癌症；第二次癌症的风险约为每5年40%，而 对于那些没有癌症史的人来说，每5年只有2%左右。初赛 对x射线照射患者的皮肤肿瘤的研究表明 P53基因可能的X射线损伤；6例基底细胞癌或上皮瘤中5例 表现出外显子7、8或9的缺失或易位损伤，以及1 6例患者外周血白细胞DNA中P53全部缺失。这个 这里提出的研究旨在回答以下问题 在这一独特的患者群体中的初步发现：1.如何 与诱癌过程中P53基因的遗传变化密切相关 与可能的致病因素(紫外线或x射线)有关，2.是p53基因 高危癌症患者外周血白细胞的变化 他们易感性增加的一个可能的遗传基础，以及3. 同一患者的多个皮肤癌起源于不同的 独立的遗传损伤。临床上出现的皮肤癌将 被取出并进行组织学检查。肿瘤DNA将被提取并 聚合酶链式反应(PCR)分析作为一种主要的定量方法 内部缺失和其他重排，而SSCP和DNA 测序将用于识别碱基对的改变。脱氧核糖核酸 指纹技术将被用来确定是否有多个 同一患者的癌症在基因上是不同的。特定外显子 将利用探针对Southern斑点进行区分 易位缺失。拟议的工作将建立类型 和P53基因改变在辐射诱导的皮肤基底细胞癌和 P53改变的类型是否可以预测对 外用5-氟尿嘧啶进行二级预防。