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: 6522523
• 负责人: Nancy B. Kiviat
• 金额: $ 52.24万
• 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/6522523
• 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）：尽管死亡率很少 这些癌症与鳞状细胞皮肤癌（SCSC）构成了主要公众 由于与治疗相关的高成本而引起的健康问题。这 紫外线辐射（UVR）暴露与发展之间的关系 但是，SCSC已建立了良好 关联尚不清楚。我们假设许多这些肿瘤是由 在通常维持遗传的基因中获取UVR诱导的突变 稳定性，尤其是p53基因中的突变以及感染 具有某些皮肤人类乳头瘤病毒（HPV）。确认这个 假设具有重大的公共卫生影响，因为如果是的，则是HPV 特定类型的疫苗（类似于现在被测试的预防疫苗 可以开发宫颈癌）并特定的p53突变（或相关 蛋白质）可以作为设计额外预防的目标 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诱导的二吡啶二聚体的形成而获得 系统，DNA序列和基于克隆的组织检查 SCSC和非静电控制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多个 SCSC组织的百分比以及多达50％的太阳暴露于非癌症 皮肤细胞。同样，免疫能力患者的小病例系列已经显示 皮肤HPV DNA存在于90％以上的SCSC病变中 多达50％的控制组织。有趣的是，我们最近的研究表明 特定皮肤HP VS的上游调节区（URR）是 通过p53蛋白与p53共有序列结合的UVR暴露激活 在一些皮肤HPV的URR中。此外，不同的p53蛋白似乎 它们激活HPV的能力有所不同。这些发现以及事实 已知皮肤HPV E6/E7蛋白会诱导增殖和克隆 受感染细胞的扩展使我们提出以下内容。我们假设 上皮细胞的UVR暴露导致嘧啶的获取 在p53基因中选择突变的二聚体，以及选择 通常维持遗传稳定性的基因中的突变。这样的细胞， 获得了“突变器表型”的潜力 积累了进展的许多突变的特征，也是必要的 癌症和消除凋亡的能力。但是，这些能力 异常细胞发展为恶性肿瘤很可能需要增加 增殖和克隆扩张。我们假设如果这种异常细胞 感染了在UVR暴露时激活的皮肤HPV类型， 这种暴露会导致HPV依赖性增殖和克隆扩张。 随后将这种细胞种群暴露于UVR，连续回合 突变，选择和依赖HPV的克隆膨胀，可能导致 与恶性发展有关的突变的积累 表型。我们建议通过进行案例对照来审查这一假设 研究和基于实验室的研究旨在提供确认 我们临床发现的生物学相关性。