FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma1. Issue 4 (11th February 2013)

• Record Type: Journal Article
• Authors: Arao, Tokuzo; Ueshima, Kazuomi; Matsumoto, Kazuko; Nagai, Tomoyuki; Kimura, Hideharu; Hagiwara, Satoru; Sakurai, Toshiharu; Haji, Seiji; Kanazawa, Akishige; Hidaka, Hisashi; Iso, Yukihiro; Kubota, Keiichi; Shimada, Mitsuo; Utsunomiya, Tohru; Hirooka, Masashi; Hiasa, Yoichi; Toyoki, Yoshikazu; Hakamada, Kenichi; Yasui, Kohichiroh; Kumada, Takashi; Toyoda, Hidenori; Sato, Shuichi; Hisai, Hiroyuki; Kuzuya, Teiji; Tsuchiya, Kaoru; Izumi, Namiki; Arii, Shigeki; Nishio, Kazuto; Kudo, Masatoshi
• Is Part Of: Hepatology. Volume 57:Issue 4(2013:Apr.)
• Page Start: 1407
• Page End: 1415
• Publication Date: 2013-02-11
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.25956
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <italic>FGF3</italic> and <italic>FGF4</italic>, was highly amplified. A real‐time polymerase chain reaction–based copy number assay revealed that <italic>FGF3</italic>/<italic>FGF4</italic> 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 (<italic>P</italic> = 0.006). Fluorescence <italic>in situ</italic> hybridization analysis confirmed <italic>FGF3</italic> amplification. In addition, the clinico‐pathological features showed that multiple lung metastases (5/13, <italic>P</italic> = 0.006) and a poorly differentiated histological type (5/13, <italic>P</italic> = 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one <italic>FGF3</italic>/<italic>FGF4</italic>‐amplified and three <italic>FGFR2</italic>‐amplified cancer cell lines exhibited hypersensitivity to sorafenib <italic>in vitro</italic>. Finally, an <italic>in vivo</italic> study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed <italic>FGF4</italic> tumors, while being less effective in tumors expressing <italic>EGFP</italic> or <italic>FGF3</italic>. <italic>Conclusion: FGF3</italic>/<italic>FGF4</italic> amplification was observed in around 2% of HCCs. Although the sample size was relatively small, <italic>FGF3/FGF4</italic> 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. (H<sc>EPATOLOGY</sc> 2013)</p> </abstract>