FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma

Abstract

The response rate to sorafenib in hepatocellular carcinoma (HCC) is relatively low (0.7%-3%), however, rapid and drastic tumor regression is occasionally observed. The molecular backgrounds and clinico-pathological features of these responders remain largely unclear. We analyzed the clinical and molecular backgrounds of 13 responders to sorafenib with significant tumor shrinkage in a retrospective study. A comparative genomic hybridization analysis using one frozen HCC sample from a responder demonstrated that the 11q13 region, a rare amplicon in HCC including the loci for FGF3 and FGF4, was highly amplified. A real-time polymerase chain reaction-based copy number assay revealed that FGF3/ FGF4 amplification was observed in three of the 10 HCC samples from responders in which DNA was evaluable, whereas amplification was not observed in 38 patients with stable or progressive disease (P 5 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico-pathological features showed that multiple lung metastases (5/13, P 5 0.006) and a poorly differentiated histological type (5/13, P 5 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one FGF3/FGF4-amplified and three FGFR2-amplified cancer cell lines exhibited hypersensitivity to sorafenib in vitro. Finally, an in vivo study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed FGF4 tumors, while being less effective in tumors expressing EGFP or FGF3. Conclusion: FGF3/FGF4 amplification was observed in around 2% of HCCs. Although the sample size was relatively small, FGF3/FGF4 amplification, a poorly differentiated histological type, and multiple lung metastases were frequently observed in responders to sorafenib. Our findings may provide a novel insight into the molecular background of HCC and sorafenib responders, warranting further prospective biomarker studies.

Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity

“…20 FGF4 gene amplification has been reported in various human cancers. [24][25][26][27] The FGF4 gene is expressed from the early stage of embryonic development in fetal life and has essential roles in cell differentiation, morphogenesis and proliferation of a variety of organizations. 28 In human adult organs, FGF4 is highly expressed in the testis.…”

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

“…The DNA copy numbers of EGFR, HER2, HER3, and HER4 were determined using commercially available and predesigned TaqMan Copy Number Assays (Applied Biosystems), as described previously (27). The primer IDs used in this study were as follows: EGFR, Hs0997424_cn (intron 14 and exon 15); HER2, Hs05475431_cn (intron 19); HER3, Hs01446234_cn (intron 21 and 22); and HER4, Hs04606638_cn (intron 18).…”

“…The HER4 point mutations were amplified using the PrimeSTAR Mutagenesis Basal Kit (TaKaRa). Viral production was performed as previously described (27). The viral vectors and stable viral transfectant cell lines were designated as pRetro-EGFP, pRetro-HER4 WT, pRetro-HER4 G1109C, pRetro-HER4 E317K, HEK293/ EGFP, HEK293/HER4 WT, HEK293/HER4 G1109C, HEK293/ HER4 E317K, NIH3T3/EGFP, NIH3T3/HER4 WT, NIH3T3/HER4 G1109C, and NIH3T3/HER4 E317K, respectively.…”

“…The tumor formation and volume were assessed twice a week. These methods have been previously described (26,27).…”

MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations

“…The tumor formation and volume were assessed every 2 to 3 days. This method has been previously described (21).…”