Identification of Flat Colorectal Cancer Modifiers

描述(申请人提供)：结直肠癌(CRC)是美国癌症死亡的第二大原因。通过常规结肠镜及早发现结直肠癌是获得良好结果的关键，然而，越来越多的证据表明，肿瘤形态可以影响检测频率。经典的息肉状病变在结肠镜检查中的发现和切除速度远远高于平坦病变，而且越来越多的证据表明，一旦发现，平坦病变具有更高的侵袭性倾向。关于不同的CRC形态是如何或为什么形成的，或者它是否是由特定的遗传或环境因素造成的，人们知之甚少。最近，新的结直肠癌小鼠模型已经被开发出来，这种模型持续且几乎完全产生扁平的结直肠肿瘤。这表明有特定的遗传宿主因素决定了结直肠癌的形态。利用这些小鼠模型，我们建议通过1)确定扁平CRC修饰基因的数量和遗传位置以及2)精细定位和识别扁平CRC修饰基因的候选基因来识别影响CRC形态的遗传因素。已经建立了两个小鼠品系之间的遗传杂交，这两个品系的CRC表型截然不同。将收集基因类型和表型数据，并对F2和回交小鼠进行统计遗传分析，以阐明包含非多倍体相关修饰基因的遗传间隔。同时，将对杂交的结肠组织进行微阵列，并进行eQTL研究，以确定修饰候选基因。 与公共健康相关：结肠癌是一个严重的公共健康问题，特别是最近的数据表明，更难发现的扁平病变比之前认为的更常见。了解控制肿瘤形态的因素将有助于确定识别它们的候选生物标记物和潜在的治疗干预新靶点。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Early detection of CRC through routine colonoscopy is critical to a favorable outcome, however there is growing evidence that tumor morphology can impact frequency of detection. Classical polypoid lesions are detected and removed during colonoscopy at a much higher rate than flat lesions, and there is growing evidence that once detected, flat lesions have a higher propensity to be invasive. Little is known about how or why different CRC morphologies form or whether it is due to specific genetic or environmental factors. Recently, novel mouse models of CRC that consistently and almost exclusively produce flat colorectal tumors have been developed. This suggests that there are specific genetic host factors that determine CRC morphology. Using these mouse models, we propose to identify the genetic factors responsible for CRC morphology by 1) determining the number and genetic locations of flat CRC modifiers and 2) fine mapping and identifying candidate genes for modifiers of flat CRCs. A genetic cross has been established between two mouse strains that develop contrasting CRC phenotypes. Genotypic and phenotypic data will be collected and a statistical genetic analysis of F2 and backcross mice will be performed to elucidate the genetic intervals containing non-polypoid associated modifiers. Concurrently, microarrays will be performed on colon tissue from the crosses and an eQTL study performed to identify modifier candidate genes. PUBLIC HEALTH RELEVANCE: Colon cancer is a serious public health problem, especially with the recent data suggesting the more difficult to detect flat lesions are more common than previously thought. Understanding the factors that control tumor morphology will aid in identifying candidate biomarkers for their identification and potential new targets for therapeutic intervention.