Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention
Ana M Bolivar1, Fahriye Duzagac1, Nan Deng1
1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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.
Insights
Lynch syndrome (LS) precancers and early cancers generate shared frameshift-neoantigens (neoAgs) that elicit T-cell responses. This discovery offers opportunities for developing vaccines to target these early-stage LS lesions.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Lynch syndrome (LS) carriers have a high rate of mismatch repair-deficient tumors with numerous neoantigens (neoAgs).
- Understanding targetable neoAgs in LS precancers is crucial for developing effective vaccines and immune-interception strategies.
- Detailed information on neoAg profiles in LS precancerous lesions is currently lacking.
Purpose of the Study:
- To characterize the somatic mutation and frameshift-neoAg landscape in colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers from LS carriers.
- To identify and validate immunogenic neoAgs within these lesions for potential therapeutic targeting.
Main Methods:
- Generated paired whole-exome and transcriptomic sequencing data from LS carrier colorectal lesions (PWOMP, precancers, advanced precancers, early-stage cancers).
- Developed a computational pipeline to predict, rank, and prioritize top neoAgs.
- Validated predicted neoAgs in vitro using ELISpot and tetramer assays.
Main Results:
- High mutation rates were observed in LS cancers (83%) and advanced precancers (63%).
- Significant numbers of MHC-I neoAgs were detected in cancers (616/sample) and advanced precancers (294/sample), but not in PWOMP.
- 65% of top predicted neoAgs were immunogenic in vitro and present in 92% of cancers and 50% of advanced precancers.
Conclusions:
- Shared frameshift-neoAgs arise early in LS carcinogenesis within unstable microsatellite loci.
- These neoAgs can induce T-cell responses, highlighting their potential for therapeutic intervention.
- This study provides a foundation for developing vaccines targeting LS precancers and early-stage cancers.
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