Topic Highlight
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Dec 21, 2013; 19(47): 8873-8879
Published online Dec 21, 2013. doi: 10.3748/wjg.v19.i47.8873
Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma
De-Leung Gu, Yen-Hsieh Chen, Jou-Ho Shih, Chi-Hung Lin, Yuh-Shan Jou, Chian-Feng Chen
De-Leung Gu, Yen-Hsieh Chen, Jou-Ho Shih, Yuh-Shan Jou, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
Yen-Hsieh Chen, Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan
De-Leung Gu, Chi-Hung Lin, Institute of Microbiology and Immunology, School of Life Science, National Yang-Ming University, Taipei 11221, Taiwan
Jou-Ho Shih, Genome and Systems Biology Degree Program, National Taiwan University, Taipei 10617, Taiwan
Chi-Hung Lin, Chian-Feng Chen, VYM Genome Research Center, National Yang-Ming University, Taipei 11221, Taiwan
Author contributions: Gu DL, Chen YH and Shih JH performed the research and contributed equally to this work; Lin CH, Jou YS and Chen CF supervised and wrote the manuscript.
Supported by The National Research Program for Biopharmaceuticals and by the National Science Council, Taiwan with grant numbers No. 101-2320-B-010-066-MY3, No. 101-2325-B-001-011 and No. 101-2320-B-001 -029-MY3
Correspondence to: Chian-Feng Chen PhD, VYM Genome Research Center, National Yang-Ming University, 155 Linong Street, Sec.2, Taipei 11221, Taiwan.
Telephone: +886-2-28267000  Fax: +886-2-28261444
Received: September 29, 2013
Revised: November 20, 2013
Accepted: December 5, 2013
Published online: December 21, 2013

High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma (HCC) cohorts confirmed previously identified frequently mutated somatic genes, such as TP53, CTNNB1 and AXIN1, and identified several novel genes with moderate mutation frequencies, including ARID1A, ARID2, MLL, MLL2, MLL3, MLL4, IRF2, ATM, CDKN2A, FGF19, PIK3CA, RPS6KA3, JAK1, KEAP1, NFE2L2, C16orf62, LEPR, RAC2, and IL6ST. Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling, Wnt/β-catenin signaling, JAK/STAT signaling, and oxidative stress play critical roles in HCC tumorigenesis. Nevertheless, because there are few druggable genes used in HCC therapy, the identification of new therapeutic targets through integrated genomic approaches remains an important task. Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain, copy number alteration (CNA) analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons, homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression. Moreover, integration of CNAs with other high-throughput genomic data, such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models, provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.

Keywords: Copy number alteration, High-density single nucleotide polymorphism arrays, Driver genes, Hepatocellular carcinoma

Core tip: In addition to detecting somatic mutations in cancer genomes with high-throughput short-read sequencing technologies, analysis of copy number alteration in hepatocellular carcinoma (HCC) cancer genomes genotyped by high density single nucleotide polymorphism arrays is a cost-effective approach to reveal genome-wide somatic alterations accumulated during tumorigenesis. Integration with other genomic data from HCC tissues derived from high-throughput short-read sequencing, proteomics, epigenomics and transcriptomics could provide lines of evidence to identify common and novel HCC genes for potential clinical applications.