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      Characterization of Hepatocellular Carcinoma Patients with FGF19 Amplification Assessed by Fluorescence in situ Hybridization: A Large Cohort Study

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          Abstract

          Background

          FGF19 amplification is a relatively novel type of genetic aberration that has been proposed to be a driver of hepatocarcinogenesis. Selective inhibitors of FGFR4, a receptor of FGF19, have been developed as targeted therapies for hepatocellular carcinoma (HCC). Despite the role of FGF19 in mediating HCC progression, the clinicopathological characterization of patients exhibiting FGF19 amplification remains unclear. Immunohistochemical staining is the simplest and most widely used method of identifying aberrations in the FGF19 gene, although its specificity is very low.

          Methods

          This study investigated the prognostic significance of FGF19 amplification in a large cohort of 989 HCC patients using fluorescence in situ hybridization (FISH), which has a high degree of specificity. In addition, FISH data from formalin-fixed, paraffin-embedded sections were compared with copy number variation (CNV) data obtained from fresh frozen sections to validate the use of FISH as a diagnostic tool.

          Results

          FGF19 amplifications were detected by FISH in 51 (5.15%) of the 989 patients, and were independently associated with poor survival and a higher risk of tumor recurrence, as well as with poor prognostic factors such as a high α-fetoprotein level, hepatitis B or C virus infection, a large tumor size, microvascular invasion, and necrosis. In addition, FGF19 amplification was associated with TP53 mutation, and was mutually exclusive with CTNNB1 mutation. The results of the FISH and CNV analyses exhibited a significant concordance rate of 96% (κ = 0.618, p < 0.001).

          Conclusions

          These data indicate that FGF19 amplification represents a unique molecular subtype associated with poor prognostic characteristics, which supports the hypothesis that the FGF19-FGFR4 signaling pathway plays an important role in hepatocarcinogenesis. We have also demonstrated that FISH is a viable alternative to CNV analysis, offering a number of advantages in the clinical setting.

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          Author and article information

          Journal
          Liver Cancer
          Liver Cancer
          LIC
          Liver Cancer
          S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch )
          2235-1795
          1664-5553
          February 2019
          22 May 2018
          1 February 2020
          : 8
          : 1
          : 12-23
          Affiliations
          aDepartment of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
          bDepartment of Biosciences, COMSATS Institute of Information and Technology, Islamabad, Pakistan
          cDepartment of Statistics, Korea University, Seoul, Republic of Korea
          dDepartment of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
          eAsan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
          fDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
          gDepartment of Hematology-Oncology, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, Republic of Korea
          Author notes
          *Sung-Min Ahn, Department of Hematology-Oncology, Gachon University Gil Medical Center, Namdong-daero, Namdong-gu, Incheon 21565 (Republic of Korea), E-Mail smahn@ 123456gachon.ac.kr , Eunsil Yu, Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43 gil, Songpa-gu, Seoul 05505 (Republic of Korea), E-Mail d890075@ 123456gmail.com

          Hyo Jeong Kang and Farhan Haq contributed equally to the work described in this paper.

          Article
          PMC6388559 PMC6388559 6388559 lic-0008-0012
          10.1159/000488541
          6388559
          30815392
          Copyright © 2018 by S. Karger AG, Basel
          Page count
          Figures: 4, Tables: 5, References: 27, Pages: 12
          Categories
          Original Paper

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