Characterizing the molecular signatures of rare inherited colon cancer syndromes

描述(申请人提供)：本申请涉及广泛的挑战领域(15)翻译科学和具体的挑战主题，15-OD(ORDR)-101：预防、早期发现和治疗罕见疾病的试点项目。目前诊断罕见遗传病的技术最常见的是识别DNA的改变。然而，这项技术是不完整的，因为错过了对致病突变的识别，并且对DNA变化导致的分子变化知之甚少。该项目建议通过在分子水平上分析目标疾病组织中实际发生的情况来接近罕见疾病。然后，一个独特的疾病标记将被用于诊断，所识别的分子途径将被用于指导靶向治疗。这可以在存在或不存在基因突变的情况下进行。这项技术正被应用于癌症诊断和治疗，并有机会将其应用于罕见疾病。将对7种罕见的结肠癌综合征进行评估，这些综合征的基因在散发性结肠癌进展中通常发生突变。这将通过分析内窥镜检查期间活检获得的新鲜结肠上皮细胞的RNA来实现，以便识别受疾病影响的初级组织的变化。通过这种微阵列技术，我们已经识别了一组48个RNA探针，它们一致地区分了对照组、FAP和AFAP正常出现的结肠组织，现在建议将这种方法扩展到包括其他罕见的结肠癌综合征。这项建议的三个目的是1)确定从七个不同罕见遗传性结肠癌综合征患者身上获取的正常结肠黏膜中独特的RNA微阵列表达特征，2)获取每个综合征中差异调控的前20个基因，以建立用于临床诊断的实时定量PCR分析，以及3)使用患者匹配的正常和肿瘤结肠组织，以确定在每个综合征中随着结肠上皮细胞过度增殖和癌变而改变的特定分子通路，并确定用于治疗的分子靶点。这项工作是翻译的，因为将开发结肠癌易感性的诊断方法，此外，还将产生关于结肠癌发病机制中涉及的遗传和分子途径的有价值的信息。项目简介：该项目建议开发一种新的方法来诊断和了解结肠癌的发展和进展。它将观察a)未受影响的人和具有结肠癌遗传易感性的人的正常结肠组织中分子信息的差异，以及b)当结肠组织开始癌变时分子信息的差异。这些差异将成为一种新的诊断测试的基础，并将确定癌症发展中的重要过程，这些过程可以作为药物治疗的靶点。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- OD(ORDR)-101: Pilot projects for prevention, early detection and treatment of rare diseases. Current technology for diagnosis of rare genetic diseases most commonly involves identification of the alteration in DNA. This technology, however, is incomplete as identification of disease causing mutations are missed and the molecular changes that result from the DNA change are poorly understood. This project proposes to approach rare diseases by analyzing what is actually happening in the target disease tissue on a molecular level. Then, in turn, a unique disease signature will be used for diagnostics and the identified molecular pathways involved used to direct targeted therapies. This can be done in the presence or absence of a genetic mutation. This technology is being applied to cancer diagnosis and treatment, and the opportunity exists to apply it to rare diseases. Seven rare colon cancer syndromes whose genes are commonly mutated in sporadic colon cancer progression will be evaluated. This will be accomplished by analyzing RNA from fresh colonic epithelia obtained as biopsies during endoscopy so that alterations in the primary tissue affected by disease can be identified. With this microarray technology, we have identified set of 48 RNA probes that consistently distinguish between control, FAP and AFAP normal appearing colonic tissue and now propose to expand this approach to include additional rare colon cancer syndromes. The three aims of this proposal are to 1) define the unique RNA microarray expression signatures in normal colonic mucosa taken from patients with seven different rare inherited colon cancer syndromes, 2) take the top 20 genes that are differentially regulated in each syndrome to develop a real time quantitative PCR assay for clinical diagnosis and 3) use patient matched normal and neoplastic colonic tissues to identify specific molecular pathways that are altered in each of the syndromes as colonic epithelial cells become hyperproliferative then cancerous and identify molecular targets for treatment. This work is translational, as diagnostic approaches for colon cancer susceptibility will be developed, and additionally, valuable information concerning the genetic and molecular pathways involved in the pathogenesis of colon cancer will be generated. Project Narrative: This project proposes to develop a new approach to diagnose and understand how colon cancer develops and progresses. It will look at differences in the molecular messages in a) normal colon tissue from unaffected people and people with an inherited predisposition to colon cancer and b) differences in molecular message when colon tissue starts to become cancerous. These differences will be the basis of a new diagnostic test and will identify important processes in cancer development that can be targeted with drugs for treatment.