Human Papilloma Virus Infection in Patients with Colorectal Cancer

结直肠癌患者的人乳头瘤病毒感染

• 批准号: 8700571
• 负责人: MARCIA Roxana CRUZ-CORREA
• 金额: $ 5.48万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-07 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700571
• 关键词: Age; Algorithms; Anogenital cancer; Biological; Blinded; Cell Cycle; Cervical; Colorectal; Colorectal Cancer; DNA; DNA Sequence; Development; Etiology; Gender; Genes; Genome; Genotype; Hematogenous Spread; High Prevalence; Hispanics; Human Genome; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Human papillomavirus 18; Individual; Infection; Laboratories; Malignant - descriptor; Matched Case-Control Study; Measures; Methods; Minority; Modeling; Molecular; Molecular Models; Mucous Membrane; Mutation; Neoplasms; Nested PCR; Non-Malignant; Pathway interactions; Patients; Play; Polyps; Population; Prevalence; Prevention strategy; Primary Carcinoma; Process; Puerto Rico; Reaction; Research Design; Risk Factors; Role; Sampling; Sexually Transmitted Diseases; Testing; Time; Tissues; Underserved Population; Viral Load result; Viral Oncogene; Virus; cancer diagnosis; carcinogenesis; colon carcinogenesis; high risk; human papilloma virus oncogene; mRNA Expression; molecular modeling; sound; tumor

DESCRIPTION (provided by applicant): The current model of colorectal carcinogenesis is characterized by a gradual accumulation of genetic alterations leading to the development of polyps, which subsequently become primary carcinomas. Recent studies have suggested that Human Papillomavirus (HPV) infections may also play a role in the development of colorectal cancer (CRC). HPV infections are the most frequently sexually transmitted diseases in the world and some evidence supports that hematogenous spread of this virus may also be possible. The association between HPV infections and the development of cervical and anogenital cancer has been clearly established. Several studies have identified the presence of HPV in colorectal tissues suggesting that infection may be associated with the development and progression of CRC. However, the possible role of HPV and the mechanistic pathways leading to colorectal carcinogenesis remain to be defined. The overall objective of this application is to detect the presence, integration status and viral load of HPV, and to determine the expression level of key HPV oncogenes (E6 and E7) to elucidate if HPV is a risk factor for CRC. Our central hypothesis is that integration of the HPV oncogenes (E6 and E7) into the human genome cause cell cycle dysregulation, leading to the development of neoplasia in colorectal tissues. The following aims have been proposed: (1) Aim 1. To assess the prevalence of HPV DNA in malignant (cases) and non- malignant (controls) colorectal tissues in order to determine if there is an association between HPV infection and CRC (using nested PCR to detect HPV-16 and HPV-18 DNA; sequencing of PCR products for HPV genotyping). (2) Aim 2. To examine the genotype distribution of HPV in colorectal tissues HPV L1 positive cases, and determine integration of HPV genes into tumor genome (using nested PCR with primers specific for HPV-16 E6/E7, and HPV-18 E6/E7 viral oncogenes; integration status assessed with quantitative Real- Time PCR). (3) Aim 3. To quantify the mRNA expression levels of the HPV-16 and HPV-18 viral oncogenes E6 and E7 in HPV-positive cases (using QRT-PCR Taqman reaction strategy). We propose to describe the relationship of HPV infection and CRC, using a sound study design and validated laboratory methods, in a well-characterized population of Hispanic patients. We anticipate that our proposal will fill an existing gap regarding the role of HPV-infection in CRC and will examine the biological mechanisms responsible for colon carcinogenesis. Identification of HPV as an etiologic factor in CRC carcinogenesis may impact current molecular models, prevention strategies and treatment algorithms.

描述（由申请人提供）：目前的结直肠癌发生模型的特征是遗传变异的逐渐积累，导致息肉的发展，随后成为原发性癌。最近的研究表明，人乳头瘤病毒（HPV）感染也可能在结直肠癌（CRC）的发展中发挥作用。HPV感染是世界上最常见的性传播疾病，一些证据支持这种病毒也可能通过血液传播。HPV感染与宫颈癌和肛门生殖器癌的发展之间的关联已经明确确立。一些研究已经确定了结直肠组织中HPV的存在，这表明感染可能与CRC的发生和进展有关。然而，HPV的可能作用和导致结直肠癌发生的机制仍有待确定。本申请的总体目标是检测HPV的存在、整合状态和病毒载量，并确定关键HPV癌基因（E6和E7）的表达水平，以阐明HPV是否是CRC的风险因素。我们的中心假设是HPV癌基因（E6和E7）整合到人类基因组中导致细胞周期失调，导致结直肠组织中肿瘤的发展。提出了以下目标：（1）目标1。评估HPV DNA在恶性（病例）和非恶性（对照）结直肠组织中的患病率，以确定HPV感染与CRC之间是否存在相关性（使用巢式PCR检测HPV-16和HPV-18 DNA; PCR产物测序进行HPV基因分型）。(2)目标2.检测大肠组织中HPV L1阳性病例的HPV基因型分布，并确定HPV基因整合到肿瘤基因组中（使用HPV-16 E6/E7和HPV-18 E6/E7病毒癌基因特异性引物的巢式PCR;使用定量真实的- Time PCR评估整合状态）。(3)目标3.定量HPV阳性病例中HPV-16和HPV-18病毒癌基因E6和E7的mRNA表达水平（使用QRT-PCR Taqman反应策略）。我们建议使用合理的研究设计和经验证的实验室方法，在特征明确的西班牙裔患者人群中描述HPV感染和CRC的关系。我们预计，我们的建议将填补现有的差距，HPV感染在CRC的作用，并将检查负责结肠癌发生的生物学机制。将HPV鉴定为CRC致癌的致病因素可能会影响当前的分子模型，预防策略和治疗算法。