Robust Predictor of Colon Cancer Risk

摘要 美国至少有50万人患有林奇综合征(LS)，这是基于一种基因的遗传 错配修复(MMR)途径中的致病变异，使它们处于结肠和其他疾病的高危状态 癌症。其中一半以上的人不知道自己的诊断，因为他们的家族史不能提供信息或 未知。基因检测对于识别这一途径中的致病变异很重要，但数量很大。 未发现致病变种或不确定意义的变种的病例，导致不明确和 结果不令人满意。随着越来越多的人寻求LS检测，测序的准确替代方案是 需要预测MMR途径中基因中致病变异的分子表型效应。风险 基于流动变量分析(FVA)的分类分数是一种新的技术，可以准确地识别 在这些途径中具有杂合生殖系致病变异的人。作为对治疗的回应 化学试剂，FVA确定修复蛋白的核定位减少和减少 在这些基因中携带致病变异的细胞中损伤感知蛋白的磷酸化。这个 由此产生的检测，癌症风险C(CR-C)，是快速、廉价和高度重复性的，可以在 循环和培养人类血细胞，从而成为新一代、无测序、独立的测试 用于诊断LS。这个STTR项目的目标是开发一种简单、快速和廉价的临床测试 将准确诊断LS，并可应用于临床实践。目标1.预测疾病发展的风险 根据CR-C检测结果判断为结肠癌。目的2.微卫星不稳定性高(MSI-)人群中LS的患病率 H)、MSI低和MSI稳定的结肠癌受试者。目标3.证明分析的有效性和 用于LS诊断的CR-C试剂盒在3个点的重复性。该产品将于#年出售给临床实验室。 与指定的良好制造规范设施商业合作伙伴合作，最初是作为 实验室开发了测试，然后作为FDA批准的测试。有几个因素将推动这种商业化 进入10亿美元的市场癌症风险评估市场：1.较低的进入和性能成本，2.更高的准确性 应用于了解结肠、子宫内膜、胃、卵巢、小肠、 胰腺癌、尿路癌、肾癌、胆管癌和脑癌。创建简化的商业CR-C工具包 会改变LS的诊断。

Summary At least 500,000 people in the United States have Lynch syndrome (LS), based on inheritance of a genetic pathogenic variant in the mismatch repair (MMR) pathway, placing them at high-risk for colon and other cancers. More than half of them is unaware of their diagnosis, because their family history is uninformative or unknown. Genetic testing is important for identifying pathogenic variants in this pathway, but in a large number of cases no pathogenic variant or a variant of uncertain significance is identified, leading to ambiguous and unsatisfactory results. As more people are seeking testing for LS, accurate alternatives to sequencing are needed to predict the molecular phenotypic effects of pathogenic variants in genes in the MMR pathway. Risk classification scores based on flow variant assays (FVAs) are a new technology that can accurately identify people with heterozygous germline pathogenic variants in these pathways. In response to treatment with chemical agents, FVAs identify decreased nuclear localization of repair proteins and decreased phosphorylation of damage-sensing proteins in cells that bear pathogenic variants in these genes. The resulting test, Cancer Risk C (CR-C), is rapid, inexpensive and highly reproducible and can be performed on circulating and cultured human blood cells, thus becoming a Next Generation, non-sequencing, standalone test for diagnosing LS. The goal of this STTR project is to develop a, simple, rapid and inexpensive clinical test that will accurately diagnose LS and can be implemented into clinical practice. Aim 1. Predict risk of developing colon cancer based on CR-C test results. Aim 2. Prevalence of LS among microsatellite instability high (MSI- H), MSI-Low and MSI-Stable subjects with colon cancer. Aim 3. Demonstrate analytical validity and reproducibility of CR-C kits for LS diagnosis at 3 sites. This product will be sold to clinical laboratories in collaboration with a designated good manufacturing practices facility commercial partner, initially as a laboratory developed test and then as an FDA approved test. Several factors will drive this commercialization into the $1B market cancer risk assessment market: 1. low entry and performance costs, 2. greater accuracy than sequencing, and 3. application to understanding risks for colon, endometrial, gastric, ovarian, small bowel, pancreatic, urinary tract, kidney, bile duct and brain cancers. The creation of simplified, commercial CR-C kits will change the diagnosis of LS.