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Oncotarget. 2017 Jun 13;8(24):38592-38601. doi: 10.18632/oncotarget.16951.

Multiplexed gene expression profiling identifies the FGFR4 pathway as a novel biomarker in intrahepatic cholangiocarcinoma.

Author information

1
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
2
Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul, Korea.
3
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
4
Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
5
Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
6
Blueprint Medicines Corporation, Cambridge, Massachusetts, USA.
7
Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Abstract

BACKGROUND:

The fibroblast growth factor receptor 4 (FGFR4) pathway is an essential regulatory component of bile acid synthesis, and its relationship with hepatocellular carcinoma (HCC) has been reported. We investigated the gene expression and clinical significance of FGFR4 and related pathways in intrahepatic cholangiocarcinoma (iCCA).

RESULTS:

The median age was 56 years (range 30-78) and 34 patients (74%) were male. Six patients (13%) had hepatitis B virus infection, with or without liver cirrhosis. Overall survival was significantly associated with FGFR4 (p = 0.004), FGF19 (p = 0.047), FGF21 (p = 0.04), and KLB (p = 0.03) expression. In the multivariate analysis with potential prognostic factors, high expression of FGF19, FGF21, and FGFR4 was significantly associated with better survival. In the analysis using the TCGA iCCA dataset, mRNA overexpression of at least 1 of the FGFR4-related genes was significantly associated with better disease-free survival (p = 0.02).

MATERIALS AND METHODS:

We assessed the expression of 98 genes in formalin-fixed paraffin embedded tumor tissue specimens from 46 patients with surgically resected iCCA using a NanoString platform. This included 10 FGF pathway genes (e.g. FGFR1-4, KLB, FGF3, 4, 19, 21, and 23), 19 distal marker genes (e.g. CYP7A1 and CYP17A1), 31 genes relevant to HCC and iCCA (e.g. AFP, TS), 18 copy number variation matched genes, and 20 control genes. Log-transformation of gene expression was performed for normalization and statistical analysis. Overall survival was correlated with gene expression (< median vs. ≥ median) using a log-rank test. The prognostic impact of FGFR4-related genes was validated using the public TCGA dataset for iCCA.

CONCLUSIONS:

Our results indicate that mRNA expression of FGFR4-related genes may be a biomarker to define the distinctive molecular phenotype of iCCA. Future preclinical and clinical validation is required to define the role of the FGFR4 pathway in iCCA.

KEYWORDS:

FGF19; FGFR4; cholangiocarcinoma; intrahepatic

PMID:
28445152
PMCID:
PMC5503556
DOI:
10.18632/oncotarget.16951
[Indexed for MEDLINE]
Free PMC Article

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