Epidemiology of HPV and p53 Mutations in NM Skin Cancer

NM 皮肤癌中 HPV 和 p53 突变的流行病学

• 批准号: 6400553
• 负责人: Nancy B. Kiviat
• 金额: $ 51.61万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6400553
• 关键词: caucasian American; clinical research; gene mutation; genetic polymorphism; human papillomavirus; human subject; neoplasm /cancer epidemiology; p53 gene /protein; radiation related neoplasm /cancer; skin neoplasms; squamous cell carcinoma; ultraviolet radiation; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): Although little mortality is associated with squamous cell skin cancer (SCSC), these cancers constitute a major public health problem due to the high costs associated with treatment. The relationship between ultraviolet radiation (UVR) exposure and development of SCSC is well established, however, the molecular biology underlying this association is unclear. We hypothesize that many of these tumors result from acquisition of UVR-induced mutations in genes that normally maintain genetic stability, and in particular mutations in the p53 gene, along with infection with certain cutaneous human papillomaviruses (HPVs). Confirming this hypothesis has significant public health implications, since, if true, HPV type-specific vaccines (similar to those now being tested for prevention of cervical cancer) could be developed and specific p53 mutations (or associated proteins) could serve as a target for the design of additional preventive therapeutics. Animal and cell culture models support a role for specific p53 mutations acquired with the formation of UVR-induced dipyrimidine dimers, however, systematic, DNA sequence and cloning based examination of tissue from incident SCSC and nonlesional control tissues has yet to be undertaken in humans. The limited available data suggest that p53 mutations might be present in over 90 percent of SCSC tissue and in up to 50 percent of sun exposed non-cancerous skin cells. Similarly, small case series in immunocompetent patients have shown that cutaneous HPV DNAs are present in over 90 percent of SCSC lesions and in up to 50 percent of control tissues. Interestingly, our recent studies show that the upstream regulatory region (URR) of specific cutaneous HP Vs is activated by UVR exposure via p53 proteins binding to a p53 consensus sequence in the URR of some cutaneous HPVs. Further, different p53 proteins appear to differ in their ability to activate HPV. These findings, along with the fact that cutaneous HPV E6/E7 proteins are known to induce proliferation and clonal expansion of infected cells, lead us to propose the following. We hypothesize that UVR exposure of epithelial cells results in acquisition of pyrimidine dimers with selection of mutations in the p53 gene, as well as selection of mutations in those genes that normally maintain genetic stability. Such cells, which have acquired a "mutator phenotype," have the potential both to accumulate the many mutations characteristic of, and necessary for, progression to cancer and the ability to abrogate apoptosis. However, the ability of these abnormal cells to progress to malignancy most likely requires increased proliferation and clonal expansion. We hypothesize that if such abnormal cells are infected with a cutaneous HPV type that is activated upon UVR exposure, that such exposure leads to HPV dependent proliferation and clonal expansion. Subsequent exposure of this population of cells to UVR, with successive rounds of mutation, selection and HPV-dependent clonal expansion, could lead to accumulation of those mutations associated with development of a malignant phenotype. We propose to examine this hypothesis by undertaking a case-control study and a laboratory based study designed to provide confirmation of the biologic relevance of our clinical findings.

描述（由申请人提供）：虽然死亡率很少 鳞状细胞皮肤癌 (SCSC)，这些癌症构成了主要的公共癌症 由于治疗费用高昂而导致健康问题。这 紫外线（UVR）暴露与发育之间的关系 SCSC 已经很成熟，然而，其背后的分子生物学 关联性尚不明确。我们假设许多这些肿瘤是由 在通常维持遗传性的基因中获得紫外线诱导的突变 稳定性，特别是 p53 基因突变以及感染 与某些皮肤人乳头瘤病毒 (HPV) 相关。确认这一点 假说具有重大的公共卫生影响，因为如果正确的话，HPV 特定类型疫苗（类似于目前正在测试的预防疫苗） 宫颈癌）可能会发展并且特定的 p53 突变（或相关 蛋白质）可以作为设计额外预防措施的目标 疗法。 动物和细胞培养模型支持特定 p53 突变的作用 然而，随着 UVR 诱导的二嘧啶二聚体的形成而获得 对事故组织进行系统性 DNA 序列和克隆检查 SCSC 和非病变对照组织尚未在人类中进行。这 有限的可用数据表明 p53 突变可能存在于 90 多种 % 的 SCSC 组织和高达 50% 暴露在阳光下的非癌组织 皮肤细胞。同样，免疫功能正常患者的小病例系列显示 皮肤 HPV DNA 存在于 90% 以上的 SCSC 病变中 高达对照组织的 50%。有趣的是，我们最近的研究表明 特定皮肤 HPV 的上游调节区 (URR) 是 通过与 p53 共有序列结合的 p53 蛋白，由 UVR 暴露激活 某些皮肤 HPV 的 URR 中。此外，不同的 p53 蛋白似乎 它们激活 HPV 的能力不同。这些发现以及事实 已知皮肤 HPV E6/E7 蛋白可诱导增殖和克隆 受感染细胞的扩增，导致我们提出以下建议。我们假设 上皮细胞的 UVR 暴露导致嘧啶的获得 二聚体与 p53 基因突变的选择，以及选择 那些通常维持遗传稳定性的基因发生突变。这样的细胞， 已经获得了“突变表型”，有潜力 积累许多进展特征和必要的突变 癌症和消除细胞凋亡的能力。然而，这些能力 异常细胞进展为恶性肿瘤很可能需要增加 增殖和克隆扩增。我们假设如果这些异常细胞 感染了皮肤 HPV 类型，该类型在 UVR 照射下被激活， 这种暴露会导致 HPV 依赖性增殖和克隆扩张。 随后将这组细胞暴露于 UVR，连续几轮 突变、选择和 HPV 依赖性克隆扩增可能导致 那些与恶性疾病发展相关的突变的积累 表型。我们建议通过进行病例对照来检验这一假设 研究和旨在提供确认的基于实验室的研究 我们的临床发现的生物学相关性。