Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:166 |
|---|---|
| Enthalten in: |
Gastroenterology - 166(2024), 5 vom: 17. Apr., Seite 787-801.e11 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bolivar, Ana M [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 23.04.2024 Date Revised 26.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1053/j.gastro.2024.01.016 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM367352168 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM367352168 | ||
| 003 | DE-627 | ||
| 005 | 20240426233559.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240121s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1053/j.gastro.2024.01.016 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1388.xml |
| 035 | |a (DE-627)NLM367352168 | ||
| 035 | |a (NLM)38244726 | ||
| 035 | |a (PII)S0016-5085(24)00052-0 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Bolivar, Ana M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.04.2024 | ||
| 500 | |a Date Revised 26.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Colorectal Cancer | |
| 650 | 4 | |a Immunoprevention | |
| 650 | 4 | |a Lynch Syndrome | |
| 650 | 4 | |a MMR Deficiency | |
| 650 | 4 | |a Neoantigen | |
| 650 | 4 | |a Systems Biology | |
| 650 | 7 | |a Antigens, Neoplasm |2 NLM | |
| 650 | 7 | |a Cancer Vaccines |2 NLM | |
| 700 | 1 | |a Duzagac, Fahriye |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Reyes-Uribe, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Kyle |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Wenhui |e verfasserin |4 aut | |
| 700 | 1 | |a Bowen, Charles M |e verfasserin |4 aut | |
| 700 | 1 | |a Taggart, Melissa W |e verfasserin |4 aut | |
| 700 | 1 | |a Thirumurthi, Selvi |e verfasserin |4 aut | |
| 700 | 1 | |a Lynch, Patrick M |e verfasserin |4 aut | |
| 700 | 1 | |a You, Y Nancy |e verfasserin |4 aut | |
| 700 | 1 | |a Rodriguez-Pascual, Jesus |e verfasserin |4 aut | |
| 700 | 1 | |a Lipkin, Steven M |e verfasserin |4 aut | |
| 700 | 1 | |a Kopetz, Scott |e verfasserin |4 aut | |
| 700 | 1 | |a Scheet, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Lizee, Gregory A |e verfasserin |4 aut | |
| 700 | 1 | |a Reuben, Alexandre |e verfasserin |4 aut | |
| 700 | 1 | |a Sinha, Krishna M |e verfasserin |4 aut | |
| 700 | 1 | |a Vilar, Eduardo |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Gastroenterology |d 1945 |g 166(2024), 5 vom: 17. Apr., Seite 787-801.e11 |w (DE-627)NLM00001706X |x 1528-0012 |7 nnns |
| 773 | 1 | 8 | |g volume:166 |g year:2024 |g number:5 |g day:17 |g month:04 |g pages:787-801.e11 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1053/j.gastro.2024.01.016 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 166 |j 2024 |e 5 |b 17 |c 04 |h 787-801.e11 | ||