VIROLOGIC/GENETIC FACTORS OF HPV NEOPLASMS

HPV 肿瘤的病毒学/遗传因素

• 批准号: 6580338
• 负责人: JAMES K. MCDOUGALL
• 金额: $ 28.07万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6580338
• 关键词: apoptosis; athymic mouse; biomarker; cervix neoplasms; chromosome aberrations; comparative genomic hybridization; gene expression; human genetic material tag; human papillomavirus; human tissue; major histocompatibility complex; metastasis; multiple primary neoplasia; neoplasm /cancer genetics; neoplastic process; nucleic acid sequence; oncogenes; polymerase chain reaction; rectum neoplasms; telomerase; tissue /cell culture; tumor suppressor genes; viral carcinogenesis

The overall aim of this project is the identification of genetic and epigenetic changes in human cells expressing human papillomaviruses (HPV) genes, with particular reference to cells expressing the E6/E7 oncogenes of HPV 16 and 18. The underlying hypothesis driving these studies is that while HPV oncogene expression initiates and maintains abnormal cell replication, by interacting with the p53 and retinoblastoma (Rb) gene products, subsequent changes in host cell gene expression, as a consequence of genetic instability, result in progression to invasive carcinoma. In conjunction with the population studies in Project #1, we will test this hypothesis in the context of virologic and genetic factors associated with primary and secondary anogenital tumors. A study of the viral integration sites in multiple tumors from the same individual, aimed at identification of the cellular sequences flanking integrated HPV DNA, will provide significant evidence for the independent origin of relatedness of multiple tumors. We will extend our current CGF studies of chromosomal changes in cervical to other anogenital tumors and to tissues from individual with multiple anogenital cancers. This analysis will identify any regions common to an initial tumor and subsequent tumors at the same or different anogenital sites. The results will be examined for relationship to other risk factors, e.g. smoking, family history, sexually transmitted disease, etc., identified in other projects in the program. We will use array methods to identify genes contributing to tumor progression, for example as potential tumor suppressor genes. Initially we will restrict these experiments to regions of chromosomes #3, #5 and #20, because these have been identified by use and others as frequently showing loss or gain in cervical carcinoma. The finding that the E6 oncogene of the high-risk viruses can induce telomerase suggest that this property could contribute to the progress of HPV-infected cervical and other epithelial cells to malignancy. The response of primary human epithelial cells to E6, in terms of the level of telomerase induction, has been shown to be variable. We will use a model system to investigate whether the extent of these variable response can be utilized as a marker of potential progression.

该项目的总体目标是鉴定表达人乳头瘤病毒（HPV）基因的人类细胞中的遗传和表观遗传变化，特别是表达HPV 16和18的E6/E7癌基因的细胞。驱动这些研究的基本假设是，虽然HPV癌基因表达通过与p53和视网膜母细胞瘤（Rb）基因产物相互作用启动并维持异常细胞复制，但由于遗传不稳定性，宿主细胞基因表达的后续变化导致进展为浸润性癌。结合项目#1中的人群研究，我们将在与原发性和继发性肛门生殖器肿瘤相关的病毒学和遗传因素的背景下检验这一假设。对同一个体多个肿瘤中病毒整合位点的研究，旨在鉴定整合的HPV DNA侧翼的细胞序列，将为多个肿瘤相关性的独立起源提供重要证据。我们将把我们目前对宫颈癌染色体变化的CGF研究扩展到其他肛门生殖器肿瘤和多个肛门生殖器癌个体的组织。该分析将识别初始肿瘤和相同或不同肛门生殖器部位的后续肿瘤共同的任何区域。将检查结果与其他风险因素的关系，例如吸烟、家族史、性传播疾病等，在项目中的其他项目中。我们将使用阵列方法来鉴定有助于肿瘤进展的基因，例如作为潜在的肿瘤抑制基因。最初，我们将这些实验限制在染色体#3，#5和#20的区域，因为这些区域已经被使用和其他人鉴定为在宫颈癌中经常显示丢失或获得。高危病毒的E6癌基因可诱导端粒酶的发现表明，这种特性可能有助于HPV感染的宫颈和其他上皮细胞向恶性发展。原代人上皮细胞对E6的反应，在端粒酶诱导水平方面，已被证明是可变的。我们将使用一个模型系统来研究这些可变反应的程度是否可以用作潜在进展的标志。