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

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.

First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma

“…Infections from hepatitis B virus or hepatitis C virus were the most common HCC etiologies. Patients with FGF19 IHC-positive tumors were more likely to have α-fetoprotein levels ≥ 400 ng/mL (P = 0.002) and trended toward being more likely to have macrovascular invasion (P = 0.13) than patients with FGF19 IHC-negative tumors, indicating that FGF19 positivity was correlated with poor prognostic factors, in line with a previous study (21).…”

“…In a recent study, FGF19 amplification was independently associated with shorter survival and a higher Cancer Research. risk of recurrence in patients with HCC and was correlated with poor prognostic factors such as high α-fetoprotein and microvascular invasion (21).…”

FGF19–FGFR4 Signaling in Hepatocellular Carcinoma

“…In our recent study, amplification of FGF19 was found to be significantly associated with cirrhosis and also increased the risk of HCC [40]. Similarly, in our other study we used the fluorescence in situ hybridization technique and found the similar oncogenic patterns of FGF19 in HCC [41]. Copy number amplification of FGF19 is also highly reported in The Cancer Genome Atlas (TCGA) data [42].…”

Acquired On-Target Clinical Resistance Validates FGFR4 as a Driver of Hepatocellular Carcinoma

“…In HCC tumors that overexpress FGF19, constitutive signaling through FGFR4 can lead to unchecked proliferation and neoplastic progression (13,14), and accordingly antibodyor small-molecule-mediated inhibition of FGFR4 reduces tumor growth in liver cancer models (15,16). These findings, coupled with the fact that FGF19 amplification is associated with a poor prognosis (17), nominate the FGF19 pathway as a driver of disease in HCC and FGFR4 as a potential therapeutic target.…”