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结直肠癌对于获得良好结果至关重要，然而越来越多的证据表明肿瘤形态会影响检测频率。经典息肉样病变在结肠镜检查中的检出率和切除率远高于扁平病变，并且越来越多的证据表明，扁平病变一旦被发现，具有更高的侵袭性倾向。对于不同的结直肠癌形态是如何或为什么形成的，以及是否由于特定的遗传或环境因素，人们知之甚少。最近，研究人员开发了一种新型的结直肠癌小鼠模型，这种模型能够持续且几乎完全产生扁平结直肠肿瘤。这表明有特定的遗传宿主因素决定结直肠癌的形态。利用这些小鼠模型，我们建议通过以下方法来确定影响CRC形态的遗传因素：1)确定扁平CRC修饰因子的数量和遗传位置；2)精细定位和鉴定扁平CRC修饰因子的候选基因。在两种小鼠株之间建立了一种遗传杂交，这两种小鼠株具有不同的结直肠癌表型。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的遗传间隔。同时，将对来自杂交的结肠组织进行微阵列检测，并进行eQTL研究以鉴定修饰候选基因。

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.