Identification of Flat Colorectal Cancer Modifiers

描述（由申请人提供）：结直肠癌（CRC）是美国癌症死亡的第二大原因。通过常规结肠镜检查早期发现CRC对于良好的结果至关重要，但是越来越多的证据表明肿瘤形态会影响检测频率。在结肠镜检查过程中，经典息肉样病变的检出和切除率比扁平病变高得多，越来越多的证据表明，一旦检出，扁平病变具有更高的侵袭性倾向。关于如何或为什么不同的CRC形态形成，或者它是否是由于特定的遗传或环境因素，我们知之甚少。最近，已经开发出了持续且几乎完全产生扁平结直肠肿瘤的新型CRC小鼠模型。这表明有特定的遗传宿主因素决定CRC形态。使用这些小鼠模型，我们建议通过1）确定平坦CRC修饰物的数量和遗传位置和2）精细定位和鉴定平坦CRC修饰物的候选基因来鉴定负责CRC形态的遗传因素。已经在两种小鼠品系之间建立了遗传杂交，这两种小鼠品系形成了相反的CRC表型。将收集基因型和表型数据，并对F2和回交小鼠进行统计遗传分析，以阐明含有非息肉相关修饰剂的遗传区间。同时，将在来自杂交的结肠组织上进行微阵列，并进行eQTL研究以鉴定修饰候选基因。 公共卫生相关性：结肠癌是一个严重的公共卫生问题，特别是最近的数据表明，更难检测的扁平病变比以前认为的更常见。了解控制肿瘤形态的因素将有助于确定候选生物标志物，以进行识别和潜在的新靶点治疗干预。

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.