Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity

• DOI: 10.1038/ncomms7120
• Publication Date: 2015-01-30T13:49:11Z
• Authors: Akihiro Fujimoto; Mayuko Furuta; Yuichi Shiraishi; Kunihito Gotoh; Yoshiiku Kawakami; Koji Arihiro; Toru Nakamura; Masaki Ueno; Shun-ichi Ariizumi; Ha Hai Nguyen; Daichi Shigemizu; Tetsuo Abe; Keith A. Boroevich; Kaoru Nakano; Aya Sasaki; Rina Kitada; Kazihiro Maejima; Yujiro Yamamoto; Hiroko Tanaka; Tetsuo Shibuya; Tatsuhiro Shibata; Hidenori Ojima; Kazuaki Shimada; Shinya Hayami; Yoshinobu Shigekawa; Hiroshi Aikata; Hideki Ohdan; Shigeru Marubashi; Terumasa Yamada; Michiaki Kubo; Satoshi Hirano; Osamu Ishikawa; Masakazu Yamamoto; Hiroki Yamaue; Kazuaki Chayama; Satoru Miyano; Tatsuhiko Tsunoda; Hidewaki Nakagawa
• Keywords: Aged, 80 and over; Male; 0301 basic medicine; Carcinoma, Hepatocellular; Liver Neoplasms; Neuropeptides; Nuclear Proteins; Middle Aged; Hepatitis; 3. Good health; Cholangiocarcinoma; DNA-Binding Proteins; Proto-Oncogene Proteins p21(ras); Cytoskeletal Proteins; 03 medical and health sciences; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Proto-Oncogene Proteins; Mutation; Humans; Female; Promoter Regions, Genetic; Aged

Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB). LCB is second in the incidence for liver cancers with and without chronic hepatitis background and more aggressive than hepatocellular carcinoma (HCC). To gain insight into its molecular alterations, we performed whole-genome sequencing analysis on 30 LCBs. Here we show, the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, whereas those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs.