Robust Predictor of Colon Cancer Risk

总结 在美国，至少有50万人患有林奇综合征（LS），这是基于遗传基因的遗传。 错配修复（MMR）途径中的致病性变体，使他们处于结肠和其他疾病的高风险中。 癌的超过一半的人不知道他们的诊断，因为他们的家族史是没有信息的， 未知基因检测对于识别这一途径中的致病性变异很重要，但在大量 的情况下，没有致病性变异或变异的不确定的意义是确定的，导致模棱两可， 不令人满意的结果。随着越来越多的人寻求LS测试，测序的准确替代品是 需要预测MMR途径中致病基因变异的分子表型效应。风险 基于流式细胞仪（FVA）的分类评分是一种新技术， 在这些途径中具有杂合子生殖系致病变异的人。针对治疗， 化学试剂，FVA鉴定修复蛋白的核定位减少， 在这些基因中携带致病性变体的细胞中，损伤感应蛋白的磷酸化。的 由此产生的测试，癌症风险C（CR-C），是快速，廉价和高度可重复的，并可以进行 循环和培养的人血细胞，从而成为下一代，非测序，独立的测试 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.预测发展风险 根据CR-C测试结果的结肠癌。目标二。LS在微卫星不稳定性高（MSI-1）人群中的患病率 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， 3个研究中心LS诊断的CR-C试剂盒的重现性。该产品将出售给临床实验室 与指定的良好生产规范机构商业合作伙伴合作，最初作为 实验室开发的测试，然后作为FDA批准的测试。几个因素将推动这种商业化 进入10亿美元的癌症风险评估市场：1。低入门和性能成本，2.更高的精度 而不是测序，以及3.应用于了解结肠，子宫内膜，胃，卵巢，小肠， 胰腺、泌尿道、肾脏、胆管和脑癌。创建简化的商业CR-C试剂盒 将改变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.