R42CA232867

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.Project narrative Cancer Risk C, a flow variant analysis to diagnose Lynch syndrome, is a Next Generation high-throughput improvement over the current standard of cancer gene panel sequencing. The increased sensitivity and specificity, lower cost, and shortened time to reporting makes testing practical even without a significant family history. This robust test will benefit health care providers and their at-risk patients.