Characterizing the molecular signatures of rare inherited colon cancer syndromes

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15- OD(ORDR)-101：预防、早期发现和治疗罕见疾病的试点项目。目前诊断罕见遗传疾病的技术最常见的是鉴定DNA的改变。然而，这项技术是不完整的，因为无法识别引起疾病的突变，而且人们对DNA变化导致的分子变化知之甚少。该项目建议通过分析目标疾病组织在分子水平上实际发生的情况来治疗罕见疾病。然后，一个独特的疾病特征将被用于诊断，并确定用于指导靶向治疗的分子途径。这可以在存在或不存在基因突变的情况下完成。这项技术正在被应用于癌症的诊断和治疗，并且存在将其应用于罕见疾病的机会。七种罕见的结肠癌综合征，其基因在散发性结肠癌进展中通常发生突变，将被评估。这将通过分析在内窥镜检查期间活检获得的新鲜结肠上皮细胞的RNA来完成，以便识别受疾病影响的原发组织的变化。利用这种微阵列技术，我们已经确定了一组48个RNA探针，可以一致地区分对照，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。该提案的三个目标是：1)定义来自7种罕见遗传性结肠癌综合征患者的正常结肠黏膜中独特的RNA微阵列表达特征；2)选取每种综合征中受差异调控的前20个基因，开发实时定量PCR检测用于临床诊断；3)利用患者匹配的正常和肿瘤结肠组织，确定每种综合征中随着结肠上皮细胞增生继而癌变而改变的特定分子通路，并确定治疗的分子靶点。这项工作是翻译的，因为结肠癌易感性的诊断方法将被开发出来，此外，有关结肠癌发病机制的遗传和分子途径的宝贵信息将被产生。项目简介：本项目提出开发一种新的方法来诊断和了解结肠癌的发生和进展。它将研究a)未受影响的人和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b)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，并将确定癌症发展的重要过程，从而可以用药物进行治疗。

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.