Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma
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Published:2024-01-29
Issue:1
Volume:22
Page:
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ISSN:1741-7015
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Container-title:BMC Medicine
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language:en
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Short-container-title:BMC Med
Author:
Yang Xu, Lian Baofeng, Zhang Nan, Long Junyu, Li Yiran, Xue Jingnan, Chen Xiangqi, Wang Yunchao, Wang Yanyu, Xun Ziyu, Piao Mingjian, Zhu Chenpei, Wang Shanshan, Sun Huishan, Song Zhijian, Lu Leilei, Dong Xiaowei, Wang Aodi, Liu Wenjin, Pan Jie, Hou Xiaorong, Guan Mei, Huo Li, Shi Jie, Zhang Haohai, Zhou Jinxue, Lu Zhenhui, Mao Yilei, Sang Xinting, Wu Liqun, Yang Xiaobo, Wang Kai, Zhao HaitaoORCID
Abstract
Abstract
Background
Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA.
Methods
We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA.
Results
Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy.
Conclusions
MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS.
Trial registration
This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).
Funder
National High Level Hospital Clinical Research Funding CAMS Innovation Fund for Medical Sciences CAMS Clinical and Translational Medicine Research Funds CSCO-hengrui Cancer Research Fund CSCO-MSD Cancer Research Fund National Ten-thousand Talent Program the Fundamental Research Funds for the Central Universities the Young Scientists Fund of the National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
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