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 (IH-CCa).

Methods: We assessed the expression of 98 genes in formalin-fixed paraffin embedded tumor tissue specimens from 46 patients with IH-CCa surgically resected using the NanoString platform. This included 10 FGF pathway genes (e.g. FGFR1-4, KLB, FGF3, 4, 19, 21, 23), 19 distal marker genes (e.g. CYP7A1, CYP17A1) and 31 genes relevant to HCC and CCa (e.g. AFP, TS) and 18 CNV matched genes and 20 control genes. Log-transformation of the gene expression was done for normalization and statistical analysis. Overall survival of 44/46 patients was correlated with gene expression (< median vs ≥ median) using a log-rank test. Two patients were excluded from analysis, due to death from postoperative complications and metastasectomy respectively.

Results: The median age of our patient cohort was 56 years (range 30-78) and 34 patients (74%) were male. All but one tumor specimen (98%) were from the primary tumor resection and microscopic complete resection (R0) was achieved in 37 patients (80%). Six patients (13%) had hepatitis B virus infection with or without liver cirrhosis. FGFR4 was expressed 100 times over background in IH-CCa, the expression of FGF19, FGF21, CYP7A1, CYP17A1, AFP and KLB was lower. Overall survival was significantly stratified according to the expression of FGFR4 (p = 0.004), FGF19 (p = 0.046), FGF21 (p = 0.04), KLB (p = 0.03), CYP8B1 (p = 0.02), ADH1B (p = 0.045), CDKN1B (p = 0.005), NCOR1 (p = 0.03), NF1 (p = 0.006), NROB2 (p = 0.001), MAP2K3 (p = 0.009), MYC (p = 0.04), CYP2E1 (p<0.001), and LGR5 (p = 0.03).

Conclusions: Our results indicate that FGFR4 might have a crucial role in IH-CCa, and its overexpression was associated with better prognosis, supporting that FGFR4 may define a subset of IH-CCa and be used as a promising target for therapeutic interventions.

Citation Format: Changhoon Yoo, Kyu-pyo Kim, Baek-Yeol Ryoo, Seung-Mo Hong, Jung Jin Hwang, Seong-Yun Jeong, Klaus Hoeflich, Oleg Schmidt-Kittler, Stephen Miller, Eun Kyung Choi. Multiplexed gene expression profiling of resected intrahepatic cholangiocarcinoma: Implication of FGFR4-FGF19 as a novel treatment target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2277.