Abstract 3890: Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity

Abstract

Abstract Primary liver cancer is the third leading cause of cancer death worldwide. Virus infection is the most common and strongest etiological factor for liver cancer development. Pathologically, primary liver cancer can be classified into ∼90% hepatocellular carcinoma (HCC), and 5∼10% intrahepatic cholangiocarcinoma (ICC), and the combined hepatocellular-cholangiocarcinoma (cHCC/CC) representing only a small portion. Clinically, ICC and cHCC/CC show much more aggressive behavior with poorer prognosis than HCC, and no standard treatment currently exists, other than surgical resection. ICC and cHCC/CC show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying a biliary phenotype (LCB). To gain insight into molecular alterations of LCBs, 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, while 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. Citation Format: Hidewaki Nakagawa, Akihiro Fujimoto, Mayuko Furuta, Kunihito Gotoh, Toru Nakamura, Masakazu Yamamoto, Hiroki Yamaue, Kazuaki Chayama, Satoru Miyano, Tatsuhiko Tsunoda. Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3890. doi:10.1158/1538-7445.AM2015-3890