Identification of Significant Race Associated Colon Cancer Drive Gene Mutations

描述（由申请人提供）：本申请涉及计划公告-癌症健康差异基础研究的探索性/发展性赠款计划。PA编号：PAR-09-160。这项拨款提案的标题是：“重大种族相关结肠癌驱动基因突变的鉴定”。该提案的目的是检验以下假设：不同种族的个体中结肠癌的驱动基因[CAN基因]突变模式不同，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。CRC是常见的癌症之一，具有归因于种族/民族病因因素的显著差异。非裔美国人的CRC发病率和死亡率明显高于白人。肿瘤CAN基因突变谱与几乎所有癌症系统中的癌症进展和临床行为直接相关。我们最近鉴定了140个CRC CAN基因，并能够根据种族遗传对CRC患者进行分子分层-以及使用患者自我声明的状态-使我们处于独特的位置，可以观察种族对癌症生物学这一基本方面的影响。此外，我们已经开发了评估患者血统对个体肿瘤CAN基因突变的影响的能力。该提案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我申报的人种进行分层。此外，这些患者将根据每个人的非洲和欧洲癌症信息标志物进行重新分类。这些研究是通过我们小组的一些不同努力实现的。我们已经建立了一个大型的，注释良好的生物储存库，其中包含过去20年来在大型医疗中心接受治疗的患者的结肠癌组织标本。这些标本中的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。在这些努力的同时，我们开发了一个基础设施和知识库，以支持高通量测序，如本提案中所设想的。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的深度。这一建议有可能显着推进对种族/民族易感性在整体癌症和CRC（第二大常见的人类癌症）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.