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Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy

INTRODUCTION: Targetable alterations such as BRAFV600E mutation and NTRK fusion are enriched in microsatellite instability-high (MSI-H) colorectal cancer (CRC). MSI-H with targetable alterations (MSI-H altered) might present unique opportunities for both targeted therapy and immunotherapy. We system...

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Autores principales: Hua, Hanju, He, Wenguang, Chen, Nan, He, Yinjun, Wu, Guosheng, Ye, Feng, Zhou, Xile, Li, Yandong, Ding, Yongfeng, Zhong, Weixiang, Teng, Lisong, Jiang, Weiqin, Sheng, Qinsong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870311/
https://www.ncbi.nlm.nih.gov/pubmed/36700211
http://dx.doi.org/10.3389/fimmu.2022.974793
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author Hua, Hanju
He, Wenguang
Chen, Nan
He, Yinjun
Wu, Guosheng
Ye, Feng
Zhou, Xile
Li, Yandong
Ding, Yongfeng
Zhong, Weixiang
Teng, Lisong
Jiang, Weiqin
Sheng, Qinsong
author_facet Hua, Hanju
He, Wenguang
Chen, Nan
He, Yinjun
Wu, Guosheng
Ye, Feng
Zhou, Xile
Li, Yandong
Ding, Yongfeng
Zhong, Weixiang
Teng, Lisong
Jiang, Weiqin
Sheng, Qinsong
author_sort Hua, Hanju
collection PubMed
description INTRODUCTION: Targetable alterations such as BRAFV600E mutation and NTRK fusion are enriched in microsatellite instability-high (MSI-H) colorectal cancer (CRC). MSI-H with targetable alterations (MSI-H altered) might present unique opportunities for both targeted therapy and immunotherapy. We systematically evaluated the molecular characteristics and immune-related features of MSI-H altered and MSI-H without targetable alterations (MSI-H wt) CRC patients in our study. METHODS: Among 1938 continuously enrolled CRC patients, 126 patients with MSI-H status (6.50%) were included in this retrospective study. Genomic and transcriptomic data were investigated by next-generation sequencing (NGS) and gene expression profiling (GEP), respectively. RESULTS: BRAFV600E, NTRK1, and FGFR2 mutations were the most frequent targetable alterations in MSI-H CRC patients. The MSI-H altered phenotype was significantly associated with older age (p< 0.001), right side (p=0.024) and females (p= 0.036). No lynch syndrome (LS) patients were identified in MSI-H altered group. The tumor mutational burden (TMB), and tumor neoantigen burden (TNB) of MSI-H altered and wt subgroups were comparable (p<0.05). Subsequently, transcriptomic study analysis further revealed MSI-H altered CRC patients were linked to an immune-active tumor microenvironment with higher levels of Teff IFN-gamma, CYT, and MERCK 18 signatures, and lower levels of the IPRES gene signature, EMT and TGF Beta signatures. In addition, case study supported MSI-H CRC patient harboring targetable alterations might also achieved a long-term disease-free survival benefit from immunotherapy. DISCUSSION: Our study preliminary revealed MSI-H altered as a novel subtype of MSI-H CRC patients with unique molecular signatures and immune-active tumor microenvironment. Given the accessibility of immune checkpoint inhibitors (ICIs) treatment, our results might provide clinical evidence for immunotherapy in MSI-H CRC patients with targetable alterations.
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spelling pubmed-98703112023-01-24 Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy Hua, Hanju He, Wenguang Chen, Nan He, Yinjun Wu, Guosheng Ye, Feng Zhou, Xile Li, Yandong Ding, Yongfeng Zhong, Weixiang Teng, Lisong Jiang, Weiqin Sheng, Qinsong Front Immunol Immunology INTRODUCTION: Targetable alterations such as BRAFV600E mutation and NTRK fusion are enriched in microsatellite instability-high (MSI-H) colorectal cancer (CRC). MSI-H with targetable alterations (MSI-H altered) might present unique opportunities for both targeted therapy and immunotherapy. We systematically evaluated the molecular characteristics and immune-related features of MSI-H altered and MSI-H without targetable alterations (MSI-H wt) CRC patients in our study. METHODS: Among 1938 continuously enrolled CRC patients, 126 patients with MSI-H status (6.50%) were included in this retrospective study. Genomic and transcriptomic data were investigated by next-generation sequencing (NGS) and gene expression profiling (GEP), respectively. RESULTS: BRAFV600E, NTRK1, and FGFR2 mutations were the most frequent targetable alterations in MSI-H CRC patients. The MSI-H altered phenotype was significantly associated with older age (p< 0.001), right side (p=0.024) and females (p= 0.036). No lynch syndrome (LS) patients were identified in MSI-H altered group. The tumor mutational burden (TMB), and tumor neoantigen burden (TNB) of MSI-H altered and wt subgroups were comparable (p<0.05). Subsequently, transcriptomic study analysis further revealed MSI-H altered CRC patients were linked to an immune-active tumor microenvironment with higher levels of Teff IFN-gamma, CYT, and MERCK 18 signatures, and lower levels of the IPRES gene signature, EMT and TGF Beta signatures. In addition, case study supported MSI-H CRC patient harboring targetable alterations might also achieved a long-term disease-free survival benefit from immunotherapy. DISCUSSION: Our study preliminary revealed MSI-H altered as a novel subtype of MSI-H CRC patients with unique molecular signatures and immune-active tumor microenvironment. Given the accessibility of immune checkpoint inhibitors (ICIs) treatment, our results might provide clinical evidence for immunotherapy in MSI-H CRC patients with targetable alterations. Frontiers Media S.A. 2023-01-09 /pmc/articles/PMC9870311/ /pubmed/36700211 http://dx.doi.org/10.3389/fimmu.2022.974793 Text en Copyright © 2023 Hua, He, Chen, He, Wu, Ye, Zhou, Li, Ding, Zhong, Teng, Jiang and Sheng https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Hua, Hanju
He, Wenguang
Chen, Nan
He, Yinjun
Wu, Guosheng
Ye, Feng
Zhou, Xile
Li, Yandong
Ding, Yongfeng
Zhong, Weixiang
Teng, Lisong
Jiang, Weiqin
Sheng, Qinsong
Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy
title Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy
title_full Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy
title_fullStr Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy
title_full_unstemmed Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy
title_short Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy
title_sort genomic and transcriptomic analysis of msi-h colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870311/
https://www.ncbi.nlm.nih.gov/pubmed/36700211
http://dx.doi.org/10.3389/fimmu.2022.974793
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