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

Hanju Hua; Wenguang He; Nan Chen; Yinjun He; Guosheng Wu; Feng Ye; Xile Zhou; Yandong Li; Yongfeng Ding; Weixiang Zhong; Lisong Teng; Weiqin Jiang; Qinsong Sheng

doi:10.3389/fimmu.2022.974793

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

Front Immunol. 2023 Jan 9:13:974793. doi: 10.3389/fimmu.2022.974793. eCollection 2022.

Authors

Hanju Hua¹, Wenguang He², Nan Chen³, Yinjun He⁴, Guosheng Wu¹, Feng Ye¹, Xile Zhou¹, Yandong Li¹, Yongfeng Ding⁵, Weixiang Zhong⁶, Lisong Teng⁷, Weiqin Jiang¹, Qinsong Sheng¹

Affiliations

¹ Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
² Department of Radiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Department of Colorectal Surgery, Yuyao Hospital of Traditional Chinese Medicine, Yuyao, China.
⁴ College of Medicine, Zhejiang University, Hangzhou, China.
⁵ Department of Medical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
⁶ Department of Pathology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
⁷ Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Abstract

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.

Keywords: GEP; MSI-H cancer; TME (tumor microenvironment); immunotherapy; targetable alterations.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colonic Neoplasms*
Female
Gene Expression Profiling
Genomics
Humans
Immunotherapy / methods
Microsatellite Instability
Retrospective Studies
Transcriptome*
Tumor Microenvironment / genetics

Grants and funding

The work was supported by Natural Science Foundation of Zhejiang Province (LGF22H160007, LY22H160045, LD21H030001, LY20H030011), National Natural Science Foundation of China (82170662) and Beijing Xisike Clinical Oncology Research Foundation (Y-Young2020-0471).