Identification of Significant Race Associated Colon Cancer Drive Gene Mutations

描述(由申请者提供)：本申请涉及计划公告--癌症健康差异基础研究探索性/发展性资助计划。PA编号：PAR-09-160。这项拨款提案的标题是：“识别与结肠癌相关的显著种族驱动基因突变”。这项建议的目的是检验这样一个假设，即不同种族的结肠癌患者的驱动基因[CAN基因]突变模式不同，反映在分子水平上这些群体在疾病流行病学、生活方式和环境暴露方面的差异。结直肠癌是一种常见的癌症，有明显的种族/民族病因差异。非裔美国人由CRC引起的发病率和死亡率明显高于高加索人口。在几乎所有的癌症系统中，肿瘤CAN基因突变谱与癌症进展和临床行为直接相关。我们最近识别了140个结直肠癌CAN基因，并根据种族遗传对结直肠癌患者进行分子分层的能力-以及使用患者自我声明的状态-使我们处于一个独特的位置，可以观察种族对癌症生物学这一基本方面的影响。此外，我们还开发了评估患者血统对单个肿瘤CAN基因突变的影响的能力。这项提案的目的将是对来自非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我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一些不同努力促成的。我们已经构建了一个大型的、注释良好的生物库，其中包含了过去20年来在一个大型医学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的石蜡包埋组织[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。在这些努力的同时，我们开发了基础设施和知识库，以支持高通量测序，如本提案中所设想的那样。这包括购买‘下一代’测序仪和聘请教员，以进一步扩大我们机构在这一领域的专业知识深度。这一建议有可能极大地促进对种族/民族易感性对整个癌症和结直肠癌的影响的理解--结直肠癌是人类第二常见的癌症。

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.