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Nat Commun. 2015 Jan 30;6:6120. doi: 10.1038/ncomms7120.

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

Author information

1
1] Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan [2] Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
2
Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
3
Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
4
Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
5
Department of Medicine &Molecular Science, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
6
Department of Anatomical Pathology, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
7
Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
8
Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan.
9
Department of Gastroenterological Surgery, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
10
1] Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan [2] Genome Analysis Laboratory, Institute of Genome Research, Vietnam Academy of Science and Technology, Hanoi Vietnam.
11
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
12
Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
13
Division of Cancer Genomics, National Cancer Center, Chuo-ku, Tokyo 104-0045, Japan.
14
Division of Molecular Pathology, National Cancer Center, Chuo-ku, Tokyo 104-0045, Japan.
15
Hepatobiliary and Pancreatic Surgery Division, National Cancer Center, Chuo-ku, Tokyo 104-0045, Japan.
16
Department of Gastroenterological Surgery, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
17
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
18
1] Department of Medicine &Molecular Science, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan [2] Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima 734-8551, Japan.
19
1] Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan [2] Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.

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.

PMID:
25636086
DOI:
10.1038/ncomms7120
[Indexed for MEDLINE]

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