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Published on: April 6, 2016
FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma
Tokuzo Arao1, Kazuomi Ueshima, Kazuko Matsumoto
1Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan.
Unlabelled:
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 = 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico-pathological features showed that multiple lung metastases (5/13, P = 0.006) and a poorly differentiated histological type (5/13, P = 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.
Insights
FGF3/FGF4 gene amplification is linked to rare, rapid responses to sorafenib in hepatocellular carcinoma (HCC). This finding may help identify patients who will benefit from this cancer treatment.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) shows a low response rate to sorafenib.
- Rapid tumor regression is occasionally observed, but its molecular basis is unclear.
- Identifying responders can improve treatment efficacy.
Purpose of the Study:
- To investigate the molecular and clinical features of sorafenib responders in HCC.
- To identify potential biomarkers for predicting response to sorafenib.
Main Methods:
- Retrospective analysis of 13 HCC responders.
- Comparative genomic hybridization and real-time PCR for gene amplification.
- Fluorescence in situ hybridization for confirmation.
- Analysis of clinico-pathological features.
- In vitro and in vivo functional assays.
Main Results:
- FGF3/FGF4 gene amplification was found in 3 of 10 evaluable HCC responders, but not in non-responders (P = 0.006).
- Responders frequently exhibited multiple lung metastases and poorly differentiated histology.
- FGF3/FGF4 or FGFR2 amplification correlated with sorafenib hypersensitivity in vitro.
- In vivo studies showed partial efficacy of sorafenib in FGF4-expressing tumors.
Conclusions:
- FGF3/FGF4 amplification is a rare event in HCC (approx. 2%) and is associated with sorafenib response.
- Poorly differentiated HCC and lung metastases are frequent in responders.
- These findings suggest FGF3/FGF4 amplification as a potential biomarker for sorafenib response in HCC, requiring further validation.
