Protecting genome integrity is vitally important for cancer prevention. Individuals with Lynch Syndrome (LS) have an 80% lifetime risk of developing cancer due to defects in a critical DNA repair mechanism known as mismatch repair, which causes their genomes to accumulate errors at a high rate in response to DNA damage. Frequent screening of this high-risk population is essential for detecting malignant tumors early enough to initiate timely and effective treatment. However, whereas colonoscopies and endoscopies can diagnose early colorectal cancers, there are no good screening options for many other highly lethal tumor types including pancreatic, brain, and ovarian cancers. Scientists in the Berger lab hypothesize that a reproducible signature of DNA damage known as microsatellite instability (MSI), which is characteristic of LS tumors, can form the basis for a pan-cancer screening test for these patients. They have shown previously that this MSI signature can be detected from circulating tumor DNA (ctDNA) in blood samples from LS patients with late-stage tumors. This approach has not been tested, however, for the identification of tumors at earlier stages. The investigators on this project will couple state-of-the-art DNA sequencing from the FDA-approved MSK-ACCESS platform with MSIsensor, a powerful machine learning algorithm, to optimize detection of ctDNA from early-stage tumors. The overarching goal of the project is to evaluate the sensitivity and specificity of this liquid biopsy approach to determine its feasibility as a screening tool for LS patients. These studies will pave the way for a blood-based test to identify tumors earlier and improve outcomes in LS patients.