Human Papillomavirus Association with Subsets of Colorectal Cancer

人乳头瘤病毒与结直肠癌亚型的关联

基本信息

批准号：
7895038
负责人：
POLLY A NEWCOMB
金额：
$ 8.8万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895038
关键词：
Address Age Anal canal Biological Cancer Etiology Cancer Family Cancerous Case-Control Studies Cells Cessation of life Characteristics Colon Colonic Neoplasms Colorectal Colorectal Cancer Colorectal Neoplasms Confidence Intervals Confounding Factors (Epidemiology)DNA DNA Sequence Data Development Diagnosis Distal Environmental Risk Factor Epithelial Epithelial Cells Exons Family history of Family-Based Registry Gender Genetic Genotype Genus Cola Growth HPV-High Risk High Prevalence Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papilloma virus infection Infection Investigation Licensure Location Logistics Malignant Neoplasms Malignant neoplasm of anus Malignant neoplasm of cervix uteri Marital Status Methods Microsatellite Instability Mutation Nature Odds Ratio Oncogenic Oncogenic Viruses Operative Surgical Procedures Papillomavirus Transforming Protein E6 Pathology Pathway interactions Play Polymerase Chain Reaction Population Prevalence Protein p53 Radiation Recruitment Activity Rectal Tumors Rectum Regression Analysis Research Personnel Risk Factors Role Sampling Sexually Transmitted Diseases Site Smoker Smoking Status TP53 gene Telephone Interviews Telomerase Testing Tissue Sample Tissues Tumor Suppressor Proteins Tumor Tissue United States Vaccines Virus Woman base burden of illness cancer risk carcinogenesis colon cancer family registry design high risk immortalized cell men neoplasm registry neoplastic non-smoker population based public health relevance sex tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Project Summary HPV is an oncogenic virus that is essential to the development of cervical cancer and is strongly associated with several other anogenital malignancies. HPV promotes oncogenesis via viral proteins E6 and E7. These interfere with tumor suppressor proteins p53 and pRb and induce telomerase, thereby immortalizing cells. Thus, HPV-related tumors infrequently contain p53 mutations. HPV DNA is present in tumor tissue of HPV- related cancers, and carcinogenesis via HPV occurs through persistent infection with "high-risk" (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82) strains of HPV. Since colorectal cancer originates in epithelial cells, and the anal canal, a site known to be associated with HPV-related malignancies, leads directly into the rectum and colon, several studies have examined colorectal neoplastic tissue for HPV DNA. Although recent case-control studies were small, with the largest study having just 72 cases, all have found positive associations between HPV and colorectal neoplasia. These studies suggest a possible association between HPV and colorectal cancer. However, further investigation is needed to validate these findings and explore the nature of this association. Since multiple pathways involving host genetics and environmental factors play roles in colorectal cancer carcinogenesis, it is likely that any association between HPV and colorectal cancer will be confined to specific subsets of colorectal cancer. Therefore, we propose to conduct a case-case comparison study of localized colorectal cancer cases to determine the association between high-risk HPV infection and tumor characteristics including: p53 mutation status, microsatellite-instability (MSI) status, and tumor location (proximal colon, distal colon and rectum). In addition, among cases of localized colorectal cancer, we will determine the association between colorectal HPV infection and personal characteristics, including: gender, age and smoking status. The proposed study will include 554 incident cases of localized colorectal cancer ages 20-74 occurring between January 1998 and June 2002 from the population-based Seattle Colorectal Cancer Family Registry (Seattle CCFR). We limited our sample to localized cases, because localized cases are often treated via surgery rather than radiation which could alter tumor DNA resulting in misclassification of p53 mutation status. For each case, investigators collected tumor tissue samples, pathology data, and data from a standardized telephone interview assessing known and suspect colorectal cancer risk factors. DNA from tumor samples was previously extracted, stored, and characterized for MSI status. We will test these DNA samples for HPV-specific DNA using polymerase chain reaction (PCR)-based methods and conduct HPV genotyping of all HPV positive samples. In addition, we will conduct DNA sequencing of tumor DNA to detect p53 mutations in exons 5-9 of the TP53 gene, where >90% of p53 mutations in cancerous cells occur. Logistic and polytomous regression analyses will be used to control for potential confounding variables and estimate odds ratios and 95% confidence intervals. PUBLIC HEALTH RELEVANCE: Project Narrative Colorectal cancer is the second leading cause of cancer death for both sexes in the United States, and in 2006 there were 148,610 new diagnoses of, and 55,170 deaths from, colorectal cancer. This study will be the first to evaluate the association between human papillomavirus (HPV) and subsets of colorectal cancer in a large, well-characterized, population-based cancer registry. With the recent licensure of an effective vaccine against HPV, it is important to characterize the total burden of disease associated with this virus.

描述（由申请人提供）：项目摘要 HPV 是一种致癌病毒，对于宫颈癌的发展至关重要，并且与其他几种肛门生殖器恶性肿瘤密切相关。 HPV 通过病毒蛋白 E6 和 E7 促进肿瘤发生。它们干扰肿瘤抑制蛋白 p53 和 pRb 并诱导端粒酶，从而使细胞永生化。因此，HPV 相关肿瘤很少含有 p53 突变。 HPV DNA存在于HPV相关癌症的肿瘤组织中，通过持续感染“高危型”（16、18、31、33、35、39、45、51、52、56、58型），可通过HPV致癌。、59、68、73、82) HPV 毒株。由于结直肠癌起源于上皮细胞，而肛管（已知与 HPV 相关恶性肿瘤相关的部位）直接通向直肠和结肠，因此多项研究检查了结直肠肿瘤组织中的 HPV DNA。尽管最近的病例对照研究规模较小，最大的研究仅涉及 72 例病例，但所有研究都发现 HPV 与结直肠肿瘤之间存在正相关。这些研究表明 HPV 与结直肠癌之间可能存在关联。然而，需要进一步调查来验证这些发现并探索这种关联的性质。由于涉及宿主遗传学和环境因素的多种途径在结直肠癌的致癌作用中发挥作用，因此 HPV 与结直肠癌之间的任何关联可能仅限于结直肠癌的特定亚型。因此，我们建议对局限性结直肠癌病例进行病例比较研究，以确定高危HPV感染与肿瘤特征之间的关联，包括：p53突变状态、微卫星不稳定性（MSI）状态和肿瘤位置（近端结肠）、远端结肠和直肠）。此外，在局限性结直肠癌病例中，我们将确定结直肠HPV感染与个人特征之间的关联，包括：性别、年龄和吸烟状况。拟议的研究将包括 1998 年 1 月至 2002 年 6 月期间发生的 554 例 20-74 岁局部结直肠癌病例，这些病例来自以人口为基础的西雅图结直肠癌家族登记处 (Seattle CCFR)。我们将样本限制在局部病例，因为局部病例通常通过手术而不是放疗进行治疗，放疗可能会改变肿瘤 DNA，导致 p53 突变状态的错误分类。对于每个病例，研究人员收集了肿瘤组织样本、病理数据和标准化电话访谈数据，评估已知和可疑的结直肠癌风险因素。先前提取、储存肿瘤样本中的 DNA，并对其 MSI 状态进行表征。我们将使用基于聚合酶链式反应 (PCR) 的方法测试这些 DNA 样本中的 HPV 特异性 DNA，并对所有 HPV 阳性样本进行 HPV 基因分型。此外，我们还将对肿瘤DNA进行DNA测序，以检测TP53基因外显子5-9的p53突变，癌细胞中>90%的p53突变发生在此处。 Logistic 和多元回归分析将用于控制潜在的混杂变量并估计优势比和 95% 置信区间。公共健康相关性：项目叙述结直肠癌是美国男女癌症死亡的第二大原因，2006 年新诊断结直肠癌 148,610 例，死亡 55,170 例。这项研究将首次在大型、特征明确、基于人群的癌症登记中评估人乳头瘤病毒 (HPV) 与结直肠癌亚型之间的关联。随着最近获得了针对 HPV 的有效疫苗的许可，了解与这种病毒相关的疾病的总负担变得非常重要。