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Nat Genet. 2016 May;48(5):500-9. doi: 10.1038/ng.3547. Epub 2016 Apr 11.

Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.

Author information

1
Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
2
Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
3
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
4
Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
5
CREST, JST, Tokyo, Japan.
6
Department of Bioinformatics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
7
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
8
Department of Medicine and Molecular Science, Hiroshima University School of Medicine, Hiroshima, Japan.
9
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
10
Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
11
Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
12
Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
13
Department of Anatomical Pathology, Hiroshima University School of Medicine, Hiroshima, Japan.
14
Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
15
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
16
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
17
Department of Pathology, Keio University School of Medicine, Shinjyuku-ku, Tokyo, Japan.
18
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
19
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
20
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
21
Department of Gastroenterological Surgery, Hiroshima University School of Medicine, Hiroshima, Japan.
22
Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
23
Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan.

Abstract

Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

PMID:
27064257
DOI:
10.1038/ng.3547
[Indexed for MEDLINE]

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