PMID- 32089411 OWN - NLM STAT- MEDLINE DCOM- 20210119 LR - 20210119 IS - 1618-0631 (Electronic) IS - 0344-0338 (Linking) VI - 216 IP - 4 DP - 2020 Apr TI - C-MET in intrahepatic cholangiocarcinoma: High-Frequency amplification predicts protein expression and a unique molecular subtype. PG - 152857 LID - S0344-0338(19)32279-4 [pii] LID - 10.1016/j.prp.2020.152857 [doi] AB - As an increasing number of gene alterations have been discovered in intrahepatic cholangiocarcinoma (ICC), molecular targets are promising for the diagnosis and treatment of distinct subpopulations carrying unique molecular signatures. C-MET amplification is associated with a variety of tumors, including ICC; however, the characteristics of this alteration have not been assessed in ICC. By determining the ratios of C-MET/chromosome enumeration probe (CEP) 7 double-colour probes, we evaluated the presence of C-MET amplification in a cohort of 133 ICC tumors by fluorescence in situ hybridization (FISH). We further determined the levels of MET protein expression by immunohistochemistry (IHC) and analyzed clinicopathologic records. Of the samples, 21 (15.8 %) had high-frequency and 41 (30.8 %) had low-frequency C-MET genetic amplification, and 71 (53.4 %) had a normal C-MET gene. There were significant differences in gross classification (p = 0.045), microscopic cholangitis (p = 0.030), mucus level in tumors (p = 0.012) and T stage (p = 0.007) between the three groups. When we combined high-frequency and low-frequency amplifications of C-MET into one group, only microscopic cholangitis (p = 0.010) and stage (p = 0.016) showed significant differences compared to normal C-MET gene expression. However, when we combined the low-frequency C-MET amplification group with the normal C-MET group and compared this combined group with the high-frequency C-MET amplification group, the high-frequency group had more younger patients (p = 0.047), had more non-mass-forming (MF)-type cases according to gross classification (p = 0.015), secreted more mucus (p = 0.002) and appeared to have a higher T stage (p = 0.031) than the combined group. For IHC results, although only cluster C-MET amplification predicted protein overexpression, high-frequency amplification was associated with more protein expression than the other genetic statuses (p = 0.000). As low-frequency C-MET amplification exhibited similar biology to that of the normal gene, we regarded high-frequency amplification of C-MET as a unique molecular subtype. It may play important roles in tumor progression and may be used as a prognostic marker for targeted therapy. CI - Copyright (c) 2020 Elsevier GmbH. All rights reserved. FAU - Pu, Xiao-Hong AU - Pu XH AD - Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China. FAU - Yue, Shen AU - Yue S AD - Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China. FAU - Wu, Hong-Yan AU - Wu HY AD - Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China. FAU - Yang, Jun AU - Yang J AD - Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China. FAU - Fan, Xiang-Shan AU - Fan XS AD - Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China. FAU - Fu, Yao AU - Fu Y AD - Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China. FAU - Ye, Qing AU - Ye Q AD - Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China. Electronic address: yeqingpathologu@163.com. FAU - Chen, Jun AU - Chen J AD - Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China. Electronic address: ichenjun@qq.com. LA - eng PT - Journal Article DEP - 20200211 PL - Germany TA - Pathol Res Pract JT - Pathology, research and practice JID - 7806109 RN - EC 2.7.10.1 (MET protein, human) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Bile Duct Neoplasms/*genetics/*pathology MH - Cholangiocarcinoma/*genetics/*pathology MH - Female MH - Gene Amplification MH - Humans MH - Male MH - Middle Aged MH - Proto-Oncogene Proteins c-met/*genetics MH - Transcriptome OTO - NOTNLM OT - C-MET OT - Clonal amplification OT - Intrahepatic cholangiocarcinoma COIS- Declaration of Competing Interest The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. EDAT- 2020/02/25 06:00 MHDA- 2021/01/20 06:00 CRDT- 2020/02/25 06:00 PHST- 2019/10/16 00:00 [received] PHST- 2020/01/10 00:00 [revised] PHST- 2020/02/10 00:00 [accepted] PHST- 2020/02/25 06:00 [pubmed] PHST- 2021/01/20 06:00 [medline] PHST- 2020/02/25 06:00 [entrez] AID - S0344-0338(19)32279-4 [pii] AID - 10.1016/j.prp.2020.152857 [doi] PST - ppublish SO - Pathol Res Pract. 2020 Apr;216(4):152857. doi: 10.1016/j.prp.2020.152857. Epub 2020 Feb 11.