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

Akihiro Fujimoto,Yuichi Shiraishi,Tetsuo Shibuya,Mayuko Furuta,Hiroki Yamaue,Tatsuhiko Tsunoda,Tatsuhiro Shibata,Rina Kitada,Kazuaki Chayama,Yoshinobu Shigekawa,Kazuaki Shimada,Keith A Boroevich,Kazihiro Maejima,Daichi Shigemizu,Hiroko Tanaka,Yoshiiku Kawakami,Hiroshi Aikata,Yujiro Yamamoto,Osamu Ishikawa,Tetsuo Abe,Terumasa Yamada,Koji Arihiro,Shigeru Marubashi,Kunihito Gotoh,Masaki Ueno,Masakazu Yamamoto,Shinya Hayami,Kaoru Nakano,Satoru Miyano,Aya Sasaki,Satoshi Hirano,Michiaki Kubo,Hideki Ohdan,Hidenori Ojima,Hidewaki Nakagawa,Tõru Nakamura ,Nguyễn Hải Hà ,Shun Ichi Ariizumi

doi:10.1038/ncomms7120

Abstract

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.

Highlights

Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB)
Primary liver cancer can be classified into B90% hepatocellular carcinoma (HCC), and 5B10% intrahepatic cholangiocarcinoma (ICC), and the combined hepatocellular cholangiocarcinoma, representing only a small portion[1,2,3]
In the present study, we comprehensively analyzed 30 LCBs by whole-genome sequencing (WGS) and RNA-seq, and compared their genomic landscapes with those of 60 HCCs. This is the first study that demonstrates the impact of chronic hepatitis and inflammation on the mutational landscape of the cancer genome and the first whole-genome comparison between LCBs and HCCs

Summary

Introduction

Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB). The presence of these phenotypes indicates the possibility that some of liver cancers can arise from liver progenitor or liver stem cell, exact cell origins of ICC and cHCC/CC are still controversial and remain to be elucidated[6,9]. This study demonstrates the first genome-wide comparison of LCBs with and without chronic hepatitis and characterizes their molecular features

Methods

Results

Conclusion