Microsatellite instability in mismatch repair proficient colorectal cancer: clinical features and underlying molecular mechanisms.

Autor:	Xu X; Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China., Liu K; Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China., Li C; Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China., Li M; Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China., Zhou X; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, PR China., Sun M; Department of Pathology, Tissue Bank, Fudan University Shanghai Cancer Center, Shanghai, PR China., Zhang L; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA., Wang S; Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China. Electronic address: wangs601@163.com., Liu F; Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: liufq021@163.com., Xu Y; Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: yexu@shmu.edu.cn.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2024 May; Vol. 103, pp. 105142. Date of Electronic Publication: 2024 Apr 30.
DOI:	10.1016/j.ebiom.2024.105142
Abstrakt:	Background: Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. Methods: From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. Findings: In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. Interpretation: This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. Funding: This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101). Competing Interests: Declaration of interests The authors declare no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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