Identification of Significant Race Associated Colon Cancer Drive Gene Mutations

描述（由申请人提供）：本申请涉及项目公告-癌症健康差异基础研究的探索性/发展性资助项目。PA号码：PAR-09-160。这项资助提案的标题是：“识别与种族相关的结肠癌驱动基因突变”。本研究的目的是验证驱动基因（CAN基因）突变模式在不同种族的结肠癌个体中存在差异的假设，这反映了这些群体在疾病流行病学、生活方式和环境暴露方面的分子水平差异。结直肠癌是一种常见的癌症，由于种族/民族的病因因素存在显著差异。非裔美国人CRC的发病率和死亡率明显高于白种人。肿瘤CAN基因突变谱与几乎所有癌症系统的癌症进展和临床行为直接相关。我们最近确定了140个CRC CAN基因，并根据种族遗产对CRC患者进行分子分层，以及使用患者自我声明的状态，这使我们处于一个独特的位置，可以研究种族对癌症生物学这一基本方面的影响。此外，我们已经开发了评估患者的祖先对个体肿瘤CAN基因突变的影响的能力。这项提议的目的是对来自非洲裔美国人和高加索人的一组匹配的crc中的140个CAN基因进行测序。这些患者最初将根据自己宣布的种族进行分层。此外，这些患者将根据每个人的非洲和欧洲血统信息标记进行重新分类。这些研究是由我们小组的许多不同努力促成的。我们已经建立了一个大型的、注释良好的生物库，其中包含了过去20年来在一家大型医疗中心接受治疗的患者的结肠癌组织标本。这些标本大多数是福尔马林固定石蜡包埋组织[FFPE]。在过去的几年里，我们致力于开发复杂的方法来提高从FFPE材料中提取DNA的可靠性。与这些努力相结合，我们开发了一个基础设施和知识库，以支持高通量测序，如本提案所设想的。这包括收购“下一代”测序仪和聘请教师，以进一步扩大我们机构在这一领域的专业知识深度。这一建议有可能显著促进对种族/民族易感性在癌症总体和结直肠癌（第二常见的人类癌症）中的影响的理解。

DESCRIPTION (provided by applicant): This application addresses the Program Announcement - Exploratory/Developmental Grants Program for Basic Research in Cancer Health Disparities. PA Number: PAR-09-160. The grant proposal is entitled: 'Identification of Significant Race Associated Colon Cancer Driver Gene Mutations'. The goal of this proposal is to test the hypothesis that patterns of driver gene [CAN gene] mutations differ among colon cancers arising in individuals of different race, reflecting at the molecular level differences in disease epidemiology, lifestyle, and environmental exposures among these groups. CRC is one of the common cancers with significant disparities attributed to racial/ethnic etiologic factors. African Americans have a significantly higher incidence of morbidity and mortality caused by CRC than the Caucasian population. Tumor CAN gene mutation profiles are directly related to cancer progression and clinical behavior in virtually all cancer systems. Our recent identification of the 140 CRC CAN genes and our ability to molecularly stratify CRC patients in terms of racial heritage - as well as using patient self-declared status - places us in a unique position to look at the influence of race on this fundamental aspect of cancer biology. Furthermore we have developed the ability to assess the influence of a patient's ancestry on individual tumor CAN gene mutations. The aim of this proposal will be to sequence the 140 CAN genes in a matched set of CRCs from African Americans and Caucasians. These patients will be initially stratified by self-declared race. Furthermore, these patients will be reclassified based on each individual's African and European Ancestry Informative Markers. These studies are enabled by a number of different efforts by our group. We have constructed a large, well-annotated, biorepository containing colon cancer tissue specimens from patients treated at a large medical center over the last 20 years. The majority of these specimens are formalin-fixed paraffin embedded tissues [FFPE]. Over the last few years we worked to develop sophisticated approaches to enhance the reliability of DNA extraction from FFPE materials. In tandem with these efforts we developed an infrastructure and knowledge base to support high throughput sequencing such as envisioned in this proposal. This includes the acquisition of a 'Next Generation' sequencer and hiring of faculty members to further extend the depth of expertise in this area at our institution. This proposal has the potential to significantly advance the understanding of the effects of racial/ethnic predisposition in cancers overall and in CRC - the second most common human cancer.