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

Hyo Jeong Kang; Farhan Haq; Chang Ohk Sung; Jene Choi; Seung-Mo Hong; Soo-Heang Eo; Hui Jeong Jeong; Jinho Shin; Ju Hyun Shim; Han Chu Lee; Jihyun An; Mi-Ju Kim; Kyu-Pyo Kim; Sung-Min Ahn; Eunsil Yu

doi:10.1159/000488541

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

Liver Cancer. 2019 Feb;8(1):12-23. doi: 10.1159/000488541. Epub 2018 May 22.

Authors

Hyo Jeong Kang¹, Farhan Haq², Chang Ohk Sung¹, Jene Choi¹, Seung-Mo Hong¹, Soo-Heang Eo³, Hui Jeong Jeong¹, Jinho Shin¹, Ju Hyun Shim⁴, Han Chu Lee⁴, Jihyun An⁴, Mi-Ju Kim⁵, Kyu-Pyo Kim⁶, Sung-Min Ahn⁷, Eunsil Yu¹

Affiliations

¹ Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
² Department of Biosciences, COMSATS Institute of Information and Technology, Islamabad, Pakistan.
³ Department of Statistics, Korea University, Seoul, Republic of Korea.
⁴ Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
⁵ Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
⁶ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
⁷ Department of Hematology-Oncology, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, Republic of Korea.

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.

Keywords: FGF19; Fluorescence in situ hybridization; Hepatocellular carcinoma; High copy number amplification; Prognosis.