Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan.
Hepatology. 2013 Apr;57(4):1407-15. doi: 10.1002/hep.25956. Epub 2013 Feb 11.
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.
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.
索拉非尼治疗肝细胞癌（HCC）的反应率相对较低（0.7%-3%），然而，偶尔会观察到肿瘤迅速和剧烈消退。这些应答者的分子背景和临床病理特征在很大程度上仍不清楚。我们在一项回顾性研究中分析了 13 名对索拉非尼有显著肿瘤退缩反应者的临床和分子背景。使用来自应答者的一个冷冻 HCC 样本进行比较基因组杂交分析表明，11q13 区域（包括 FGF3 和 FGF4 基因座的 HCC 罕见扩增子）高度扩增。实时聚合酶链反应基于拷贝数测定显示，在可评估 DNA 的 10 名应答者中的 3 名 HCC 样本中观察到 FGF3/FGF4 扩增，而在 38 名稳定或进展性疾病患者中未观察到扩增（P=0.006）。荧光原位杂交分析证实了 FGF3 扩增。此外，临床病理特征显示，在应答者中，经常观察到多个肺转移（5/13，P=0.006）和低分化组织学类型（5/13，P=0.13）。生长抑制测定表明，仅一个 FGF3/FGF4 扩增和三个 FGFR2 扩增的癌细胞系在体外对索拉非尼表现出高度敏感性。最后，体内研究表明，低剂量索拉非尼治疗稳定和外源性表达 FGF4 的肿瘤部分有效，而对表达 EGFP 或 FGF3 的肿瘤效果较差。
FGF3/FGF4 扩增在大约 2%的 HCC 中观察到。尽管样本量相对较小，但在索拉非尼应答者中经常观察到 FGF3/FGF4 扩增、低分化组织学类型和多个肺转移。我们的发现可能为 HCC 和索拉非尼应答者的分子背景提供新的见解，值得进一步进行前瞻性生物标志物研究。
