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

Authors

Ana M Bolivar
Fahriye Duzagac
Nan Deng
Laura Reyes-Uribe
Kyle Chang
Wenhui Wu
Charles M Bowen
Melissa W Taggart
Selvi Thirumurthi
Patrick M Lynch
Y Nancy You
Jesus Rodriguez-Pascual
Steven M Lipkin
Scott Kopetz
Paul Scheet
Gregory A Lizee
Alexandre Reuben
Krishna M Sinha
Eduardo Vilar

Publication Date

5-1-2024

Journal

Gastroenterology

DOI

10.1053/j.gastro.2024.01.016

PMID

38244726

PMCID

PMC11034773

PubMedCentral® Posted Date

5-1-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, Colorectal Neoplasms, Hereditary Nonpolyposis, Antigens, Neoplasm, Frameshift Mutation, Exome Sequencing, Female, Mutation, Male, Middle Aged, DNA Mismatch Repair, Microsatellite Repeats, Microsatellite Instability, Colorectal Neoplasms, Adult, Cancer Vaccines, Lynch Syndrome, Colorectal cancer, Neoantigen, Immunoprevention, MMR deficiency, Systems Biology

Published Open-Access

yes

Recommended Citation

Bolivar, Ana M; Duzagac, Fahriye; Deng, Nan; et al., "Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention" (2024). Faculty, Staff and Student Publications. 4634.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4634