AI Article Synopsis
- Lynch syndrome (LS) carriers develop certain types of tumors characterized by high rates of neoantigens, but information on targetable neoantigens from precancerous lesions is lacking, which is important for vaccine development.
- Researchers sequenced genetic data from various stages of colorectal lesions in LS carriers to identify and rank the top 100 mutated neoantigens, validating their findings using specific laboratory assays.
- The findings showed that while cancers and advanced precancers have numerous neoantigens, precancers exhibit fewer, with a significant proportion of the predicted neoantigens being able to prompt immune responses, suggesting potential for developing targeted vaccines against LS-related precancers and early-stage cancers.
Article Abstract
Background & Aims: Lynch syndrome (LS) carriers develop mismatch repair-deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers 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 (PWOMP), precancers, and early-stage cancers in LS carriers.
Methods: We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, 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.
Results: Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8 and memory CD4 T cells in mismatch repair-deficient cancers and precancers via transcriptomics analysis.
Conclusions: Shared 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 precancers and early-stage cancers.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11034773 | PMC |
| http://dx.doi.org/10.1053/j.gastro.2024.01.016 | DOI Listing |
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