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Theranostics. 2018 Feb 12;8(6):1740-1751. doi: 10.7150/thno.22010. eCollection 2018.

Genomic analysis of liver cancer unveils novel driver genes and distinct prognostic features.

Author information

1
Institute of Digestive Diseases and Department of Medicine & Therapeutics, State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
2
Public Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China.
3
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong.
4
Beijing Genomics Institute-Shenzhen, Shenzhen 518083, Guangdong, People's Republic of China.
5
James D. Watson Institute of Genome Sciences, 310058, Hangzhou, People's Republic of China.
6
Department of Clinical Oncology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
7
Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong.

Abstract

Objective: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease with a dismal prognosis. However, driver genes and prognostic markers in HCC remain to be identified. It is hoped that in-depth analysis of HCC genomes in relation to available clinicopathological information will give rise to novel molecular prognostic markers. Methods: We collected genomic data of 1,061 HCC patients from previous studies, and performed integrative analysis to identify significantly mutated genes and molecular prognosticators. We employed three MutSig algorithms (MutSigCV, MutSigCL and MutSigFN) to identify significantly mutated genes. The GISTIC2 algorithm was used to delineate focally amplified and deleted genomic regions. Nonnegative matrix factorization (NMF) was utilized to decipher mutational signatures. Kaplan-Meier survival and Cox regression analyses were used to associate gene mutation and copy number alteration with survival outcome. Logistic regression model was applied to test association between gene mutation and mutational signatures. Results: We discovered 11 novel driver genes, including RNF213, VAV3 and TNRC6B, with mutational prevalence ranging from 1% to 3%. Seven mutational signatures were also identified in HCC, some of which were associated with mutations of classical driver genes (e.g., TP53, TERT) as well as alcohol consumption. Focal amplifications of TERT and other druggable targets, including AURKA, were also revealed. Targeting AURKA by a small-molecule inhibitor potently induced apoptosis in HCC cells. We further demonstrated that HCC patients with TERT amplification displayed shortened overall survival independent of other clinicopathological parameters. In conclusion, our study identified novel cancer driver genes and prognostic markers in HCC, reiterating the translational importance of omics data in the precision medicine era.

KEYWORDS:

HCC; TERT; druggable target; mutation; prognostic marker

PMID:
29556353
PMCID:
PMC5858179
DOI:
10.7150/thno.22010
[Indexed for MEDLINE]
Free PMC Article

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