title: Targeted DNA and RNA sequencing of fine-needle biopsy FFPE specimens in patients with unresectable hepatocellular carcinoma treated with sorafenib.
abstract: The multi-kinase inhibitor sorafenib is now used as standard therapy for advanced hepatocellular carcinoma (HCC). Predictive biomarkers of response to sorafenib are thus necessary. The purpose of this study was to assess the feasibility of using targeted DNA and RNA sequencing to elucidate candidate biomarkers of sorafenib response using fine-needle biopsy, formalin-fixed paraffin-embedded (FFPE) specimens in patients with HCC. Targeted DNA and RNA deep sequencing were feasible for the evaluation of fine-needle biopsy FFPE specimens obtained from 46 patients with HCC treated with sorafenib. Frequent mutations of suppressor genes, such as CTNNB1 (34.8%) and TP53 (26.1%), were detected in the HCC tumors. After excluding these suppressor genes, the average numbers of detected oncogene mutations differed significantly between the non-PD and PD groups (P = 0.0446). This result suggests that the oncogene mutational burden in the tumor might be associated with the clinical response to sorafenib. We have identified candidate gene expression (TGFa, PECAM1, and NRG1) in tumor for the prediction of sorafenib response and PFS by RNA sequencing. Our findings provide new insights into biomarkers for sorafenib therapy and allow us to discuss future therapeutic strategies.
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Ohono-Higashi, Osaka-Sayamashi, Osaka, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.|Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Shogoin-Kawaharacho, Kyoto, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nishijima
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya Daini Red Cross Hospital, Nagoya City, Japan.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Orito
authors.affiliation: Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, Matsuyama City, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Joko
authors.affiliation: Department of Gastroenterology, Matsue Red Cross Hospital, Matsue City, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan.
authors.forename: Namiki
authors.initials: N
authors.lastname: Izumi
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Ohono-Higashi, Osaka-Sayamashi, Osaka, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Osaki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D044963:Biopsy, Fine-Needle; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D005557:Formaldehyde / Q000737:chemistry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020890:Neuregulin-1 / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016612:Paraffin Embedding; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D000077157:Sorafenib; D016211:Transforming Growth Factor alpha / Q000235:genetics; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C094131:NRG1 protein, human; D020890:Neuregulin-1; D010671:Phenylurea Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C587886:TGFA protein, human; C495901:TP53 protein, human; D016211:Transforming Growth Factor alpha; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D005557:Formaldehyde; D009536:Niacinamide; D000077157:Sorafenib
keywords: hepatocellular cancer; mutation; response; sorafenib