Genetic Alterations In Rodent Cancer

细胞和分子病理学分部的科学家正在与NTP/NIEHS的科学家合作，通过全基因组分析和其他遗传方法，在B6C3F1小鼠和NTP大鼠模型中自发和化学诱导的肿瘤最常见的部位，通过全基因组分析和其他遗传方法，确定癌基因和抑癌基因以及可能在癌症中发挥作用的主要基因的遗传变化。目的是增加我们对在我们的标准啮齿动物模型暴露于环境化学品后发现的肿瘤发病率增加的重要性的理解。了解在化学诱导的啮齿动物肿瘤中存在的遗传改变或基因组改变的光谱，它们在从癌前病变到肿瘤进展过程中的时间表现，以及这些因素可能与组织到组织和化学到化学的不同方式，将为区分自发和化学诱导的肿瘤提供分子基础。这种方法主要是通过内部协作实现的。从前瞻性和回溯性研究中，从对照和化学处理的啮齿动物的肿瘤中分离出DNA和RNA，并使用基于PCR的分析和基因组分析来分析遗传变化。从以前的生物分析中确定肿瘤中的特定基因变化的回溯性研究主要通过基于聚合酶链式反应的分析或全基因组分析来检查档案材料。这些研究旨在将特定的化学特性(结构特征/遗传毒性/新陈代谢)与特定目标器官的癌前病变和肿瘤性病变的遗传改变谱特征相关联。这提供了一个比较化学物质类别的机会，评估一个化学物质类别内的结构/活性关系，以及评估特定目标组织对不同化学物质的反应，而不必重复长期研究。更重要的是，NTP研究产生的数据提供了对癌症及其与人类的相关性的分子理解。

A systematic effort is being made by Cellular and Molecular Pathology Branch scientists in collaboration with NTP/NIEHS scientists to identify genetic alterations in oncogenes and tumor suppresser genes and major genes which may play a role in cancer by genome wide analysis and other genetic methods in the most frequent sites for spontaneous and chemical-induced neoplasms in B6C3F1 mice and NTP rat models. The goal is to increase our understanding of the significance of increased incidence of neoplasms that are found following exposure of our standard rodent models to environmental chemicals. Knowledge of the spectrum of genetic alterations or genomic alterations that are present in chemically induced rodent tumors, their temporal appearance in the progression from preneoplastic lesions to neoplasms, and the way in which these factors may differ from tissue-to-tissue and chemical-to-chemical, will provide a molecular basis for distinguishing between spontaneous and chemically induced neoplasms. The approach is accomplished primarily from in-house collaborations. DNA and RNA are isolated from neoplasms in control and chemically treated rodents from prospective and retrospective studies and analyzed for genetic alterations using PCR based assays and genomic analysis. Retrospective studies to identify specific genetic alterations in neoplasms from previous bioassays involve examination of archival material primarily through PCR-based assays or genome wide analysis. These studies are being designed to correlate chemical-specific properties (structural features/genotoxicity/metabolism) with characteristics of the spectrum of genetic alterations present in preneoplastic and neoplastic lesions of specific target organs. This provides an opportunity to compare classes of chemicals, to evaluate structure/activity relationships within a class, and to evaluate the response of specific target tissues to different chemicals, without having to repeat the long-term studies. More importantly the data generated from NTP studies provide a molecular understanding of cancer and its relevance to humans.