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Published on: March 14, 2019
Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies
Hanju Hua1, Wenguang He2, Nan Chen3
1Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
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.
Insights
Microsatellite instability-high (MSI-H) colorectal cancer (CRC) with targetable alterations presents a unique subtype. These patients exhibit an immune-active tumor microenvironment, suggesting potential benefits from immunotherapy.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Microsatellite instability-high (MSI-H) colorectal cancer (CRC) can harbor targetable alterations like BRAFV600E mutations and NTRK fusions.
- These targetable alterations may influence treatment strategies, including targeted therapy and immunotherapy.
Purpose of the Study:
- To systematically evaluate the molecular characteristics and immune-related features of MSI-H CRC patients with (MSI-H altered) and without (MSI-H wt) targetable alterations.
- To identify unique molecular signatures and immune microenvironment profiles associated with targetable alterations in MSI-H CRC.
Main Methods:
- Retrospective analysis of 126 MSI-H CRC patients from a cohort of 1938.
- Genomic and transcriptomic data analyzed using next-generation sequencing (NGS) and gene expression profiling (GEP).
Main Results:
- BRAFV600E, NTRK1, and FGFR2 were frequent targetable alterations in MSI-H CRC.
- MSI-H altered CRC was associated with older age, right-sided tumors, and females; no Lynch syndrome patients were identified in this group.
- MSI-H altered CRC showed an immune-active tumor microenvironment with higher Teff IFN-gamma, CYT, MERCK 18 signatures, and lower IPRES, EMT, TGF Beta signatures, despite comparable tumor mutational burden (TMB) and tumor neoantigen burden (TNB) to MSI-H wt.
Conclusions:
- MSI-H altered CRC represents a novel subtype characterized by distinct molecular signatures and an immune-active tumor microenvironment.
- Findings suggest potential clinical utility of immunotherapy for MSI-H CRC patients with targetable alterations, supported by case study of long-term disease-free survival.
