Abstract 4096: Comparative molecular profiling of sporadic and Lynch syndrome MSI tumors: Unraveling insights for vaccine design

Abstract

Abstract Lynch Syndrome (LS) is a hereditary syndrome that predisposes carriers to colorectal cancer (CRC). The hallmark of LS is microsatellite instability (MSI), resulting from a defective DNA mismatch repair (MMR) system. MSI cases have hyper-elevated frameshift mutation rates including “shared” hotspot mutations recurrently across patients. Frameshift mutations can generate neopeptides that activate the immune system. These open the door for preventive vaccines. However, preventive vaccines work best with neopeptides that happen early during tumorigenesis. Here we present 83 newly sequenced adenomas and carcinomas from Lynch syndrome carriers and combine them with previously published 68 Lynch cases and 133 Sporadic cases, thus generating the largest currently available colorectal neoplasia MSI cohort. We leveraged this large cohort to analyze the molecular landscape of adenomas vs carcinoma tumors and Lynch vs sporadic tumors. Employing our recently developed MSIDetect tool on our WGS samples, we identified microsatellite instability in 75% of adenomas, which is higher than previously reported. We found that about 30% of normal adjacent tissues showed MSI, suggesting early mismatch repair defects. This early MSI occurrence supports the potential effectiveness of preventive vaccines. We observed comparable levels of SNVs, microsatellite Indels, and single base signature activity among Lynch adenomas and carcinomas, as well as sporadic carcinomas while adjusting for variations in coverage across different datasets. Moreover, using RNA sequencing data and PCA analysis we found that adenoma and carcinoma cluster together. This large cohort enabled us to identify (as fast as we know for the first time) MS-indels that tend to have a second MS-indel in the same locus. The high similarities observed between Lynch and sporadic tumors allow for their combination in one vaccine. Using the combined MSI cohort we generated a set of about 300 neopeptides that emerged from frequent mutations (>5% in our cohort) with a strong binding affinity for at least one HLA type. We evaluated that a set of about 60 neopeptides per person from that list is predicted likely to initiate an immune response in ~99.5% of the carriers. These findings hold promise for the development of a preventive vaccine capable of targeting early tumorigenic stages. This work is approved under Weill Cornell IRB exemption 1810019672. Citation Format: Hagay Ladany, Mark Grossman, Julian Hess, Nicole Lu, Derin Keskin, Catherine J. Wu, Nir Hacohen, Richard Gallon, John Burn, Heather Hampel, Zsofia Stadler, Gad Getz, Yosef E. Maruvka, Steven Lipkin. Comparative molecular profiling of sporadic and Lynch syndrome MSI tumors: Unraveling insights for vaccine design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4096.