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Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention.
- Source :
-
Gastroenterology [Gastroenterology] 2024 May; Vol. 166 (5), pp. 787-801.e11. Date of Electronic Publication: 2024 Jan 18. - Publication Year :
- 2024
-
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.<br />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.<br />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 <superscript>+</superscript> and memory CD4 <superscript>+</superscript> T cells in mismatch repair-deficient cancers and precancers via transcriptomics analysis.<br />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.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Female
Mutation
Male
Middle Aged
DNA Mismatch Repair genetics
Microsatellite Repeats
Microsatellite Instability
Colorectal Neoplasms genetics
Colorectal Neoplasms immunology
Colorectal Neoplasms prevention & control
Adult
Cancer Vaccines immunology
Cancer Vaccines therapeutic use
Colorectal Neoplasms, Hereditary Nonpolyposis genetics
Colorectal Neoplasms, Hereditary Nonpolyposis immunology
Antigens, Neoplasm immunology
Antigens, Neoplasm genetics
Frameshift Mutation
Exome Sequencing
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 166
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 38244726
- Full Text :
- https://doi.org/10.1053/j.gastro.2024.01.016