Combined Genomic and Transcriptomic Analysis of Lynch Syndrome Colorectal Neoplasia Identifies Recurrent Shared Mutated Neoantigens for Immune Interception

Lynch syndrome (LS) carriers develop mismatch repair (MMR) deficient tumors, which generate high loads of neoantigens (neoAgs) and subsequent immune activation. Paired whole exome and transcriptomic sequencing data from colorectal lesions (13 cancers and 61 pre-cancers) of an institutional LS cohort (N=46) were used to identify recurrent and shared neoAgs derived from insertion-deletion mutations in microsatellites. We observed that mutation burden is positively correlated with neoAgs load across different stages of carcinogenesis. A custom computational pipeline was used to rank candidate neoags based on their recurrency and predicted immunogenicity. We demonstrated that 65% of our top predicted neoAgs demonstrated to be immunogenic in vitro via ELISpot assays. Our transcriptomic results revealed increased infiltration of CD8+ and CD4+ T-cells in MMR deficient lesions. Overall, our detailed description of the neoAgs and somatic mutation landscape improve our understanding of MMR deficient carcinogenesis and facilitate the development of future neoAgs-based vaccine strategies for cancer immune interception in LS patients.