Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention

Abstract

Background & AimsLynch syndrome (LS) carriers develop mismatch repair deficient (MMRd) neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS pre-cancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMPs), pre-cancers and early-stage cancers in LS carriers. MethodsWe generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMPs, 41 pre-cancers, 8 advanced pre-cancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. ResultsMutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced pre-cancers, and 20% of pre-cancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced pre-cancers, and 107 in pre-cancers. No neoAgs were detected in PWOMPs. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced pre-cancers, and 29% of pre-cancers. We observed increased levels of naïve CD8+ and memory CD4+ T-cells in MMRd cancers and pre-cancers via transcriptomics analysis. ConclusionsShared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS pre-cancers and early-stage cancers.