title: Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment.
abstract: The multi-kinase inhibitor sorafenib is clinically approved for the treatment of patients with advanced hepatocellular carcinoma (HCC). We previously reported that fibroblast growth factor 3 and 4 (FGF3/FGF4) amplification is a predictor of a response to sorafenib. This study aims to analyze the relationship between FGF-FGF receptor (FGFR) genetic alterations and the response to sorafenib. Formalin-fixed, paraffin-embedded tissue specimens from HCC patients who had achieved a complete response (CR, N=6) or non-CR (N=39) to sorafenib were collected and were examined for FGF-FGFR gene alterations using next generation sequencing and copy number assay. FGFR mutations were detected in 5 of 45 (11.1%) cases. There was no significant association between FGFR mutation status and the response to sorafenib. We detected no increase in the FGF3/FGF4 copy number in CR cases. An FGF19 copy number gain was detected more frequently among CR cases (2/6, 33.3%) than among non-CR cases (2/39, 5.1%) (P = 0.024, Chi-squared test). In conclusion, a copy number gain for FGF19 may be a predictor of a response to sorafenib, in addition to FGF3/FGF4 amplification.
authors.affiliation: Department of Surgery, Hirakata Hospital, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kaibori
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osakasayama, Osaka, 589-8511, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Surgery, Hirakata Hospital, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Morihiko
authors.initials: M
authors.lastname: Ishizaki
authors.affiliation: Department of Surgery, Hirakata Hospital, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Matsushima
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osakasayama, Osaka, 589-8511, Japan.
authors.forename: Marco A
authors.initials: MA
authors.lastname: De Velasco
authors.affiliation: Department of Surgery, Hirakata Hospital, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Matsui
authors.affiliation: Department of Surgery, Hirakata Hospital, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Iida
authors.affiliation: Department of Surgery, Hirakata Hospital, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitade
authors.affiliation: Department of Surgery, Hirakata Hospital, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.
authors.forename: A-Hon
authors.initials: AH
authors.lastname: Kwon
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Department of Surgery, Kinki University Faculty of Medicine, Osakasayama, Osaka, 589-8511, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Haji
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Osaka City General Hospital, Miyakojima, Osaka, 534-0024, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Osaka City General Hospital, Miyakojima, Osaka, 534-0024, Japan.
authors.forename: Akishige
authors.initials: A
authors.lastname: Kanazawa
authors.affiliation: Department of Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo, 660-8511, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, 558-8585, Japan.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Takemura
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, 558-8585, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Kubo
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osakasayama, Osaka, 589-8511, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D018628:Gene Dosage; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D012074:Remission Induction; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: C117476:FGF19 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D009536:Niacinamide; D005346:Fibroblast Growth Factors; D000077157:Sorafenib
keywords: FGF19; copy number gain; hepatocellular carcinoma; sorafenib