PMID- 38369190 OWN - NLM STAT- MEDLINE DCOM- 20240422 LR - 20240422 IS - 1530-0285 (Electronic) IS - 0893-3952 (Linking) VI - 37 IP - 4 DP - 2024 Apr TI - Unraveling the Significance of MET Focal Amplification in Lung Cancer: Integrative NGS, FISH, and IHC Investigation. PG - 100451 LID - S0893-3952(24)00031-0 [pii] LID - 10.1016/j.modpat.2024.100451 [doi] AB - MET amplification (METamp) represents a promising therapeutic target in non-small cell lung cancer, but no consensus has been established to identify METamp-dependent tumors that could potentially benefit from MET inhibitors. In this study, an analysis of MET amplification/overexpression status was performed in a retrospectively recruited cohort comprising 231 patients with non-small cell lung cancer from Shanghai Chest Hospital (SCH cohort) using 3 methods: fluorescence in situ hybridization (FISH), hybrid capture-based next-generation sequencing, and immunohistochemistry for c-MET and phospho-MET. The SCH cohort included 130 cases known to be METamp positive by FISH and 101 negative controls. The clinical relevance of these approaches in predicting the efficacy of MET inhibitors was evaluated. Additionally, next-generation sequencing data from another 2 cohorts including 22,010 lung cancer cases were utilized to examine the biological characteristics of different METamp subtypes. Of the 231 cases, 145 showed MET amplification/overexpression using at least 1 method, whereas only half of them could be identified by all 3 methods. METamp can occur as focal amplification or polysomy. Our study revealed that the inconsistency between next-generation sequencing and FISH primarily occurred in the polysomy subtype. Further investigations indicated that compared with polysomy, focal amplification correlated with fewer co-occurring driver mutations, higher protein expressions of c-MET and phospho-MET, and higher incidence in acquired resistance than in de novo setting. Moreover, patients with focal amplification presented a more robust response to MET inhibitors compared with those with polysomy. Notably, a strong correlation was observed between focal amplification and programmed cell death ligand-1 expression, indicating potential therapeutic implications with combined MET inhibitor and immunotherapy for patients with both alterations. Our findings provide insights into the molecular complexity and clinical relevance of METamp in lung cancer, highlighting the role of MET focal amplification as an oncogenic driver and its feasibility as a primary biomarker to further investigate the clinical activity of MET inhibitors in future studies. CI - Copyright (c) 2024 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Xiang, Chan AU - Xiang C AD - Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Lv, Xinze AU - Lv X AD - Burning Rock Biotech, Guangzhou, China. FAU - Chen, Ke AU - Chen K AD - Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Guo, Lianying AU - Guo L AD - Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Zhao, Ruiying AU - Zhao R AD - Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Teng, Haohua AU - Teng H AD - Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Ye, Min AU - Ye M AD - Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Kuang, Ting AU - Kuang T AD - Burning Rock Biotech, Guangzhou, China. FAU - Hou, Ting AU - Hou T AD - Burning Rock Biotech, Guangzhou, China. FAU - Liu, Chenglin AU - Liu C AD - Burning Rock Biotech, Guangzhou, China. FAU - Du, Haiwei AU - Du H AD - Burning Rock Biotech, Guangzhou, China. FAU - Zhang, Zhou AU - Zhang Z AD - Burning Rock Biotech, Guangzhou, China. Electronic address: zhou.zhang@brbiotech.com. FAU - Han, Yuchen AU - Han Y AD - Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: ychan@cmu.edu.cn. LA - eng PT - Journal Article DEP - 20240216 PL - United States TA - Mod Pathol JT - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc JID - 8806605 RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) SB - IM MH - Humans MH - *Lung Neoplasms/pathology MH - *Carcinoma, Non-Small-Cell Lung/genetics MH - Retrospective Studies MH - In Situ Hybridization, Fluorescence MH - Mutation MH - China MH - Proto-Oncogene Proteins c-met/genetics/metabolism MH - Chromosome Aberrations MH - Gene Amplification OTO - NOTNLM OT - MET amplification (METamp) OT - MET inhibitors OT - focal amplification OT - lung cancer EDAT- 2024/02/19 00:42 MHDA- 2024/04/22 06:43 CRDT- 2024/02/18 19:18 PHST- 2023/10/20 00:00 [received] PHST- 2024/01/24 00:00 [revised] PHST- 2024/02/04 00:00 [accepted] PHST- 2024/04/22 06:43 [medline] PHST- 2024/02/19 00:42 [pubmed] PHST- 2024/02/18 19:18 [entrez] AID - S0893-3952(24)00031-0 [pii] AID - 10.1016/j.modpat.2024.100451 [doi] PST - ppublish SO - Mod Pathol. 2024 Apr;37(4):100451. doi: 10.1016/j.modpat.2024.100451. Epub 2024 Feb 16.