Identification of Driver Genes in Hepatocellular Carcinoma by Exome Sequencing

Cleary, S. P., Jeck, W. R., Zhao, X. B., Chen, K., Selitsky, S. R., Savich, G. L., Tan, T. X., Wu, M. C., Getz, G., Lawrence, M. S., Parker, J. S., Li, J. Y., Powers, S., Kim, H., Fischer, S., Guindi, M., Ghanekar, A., Chiang, D. Y. (November 2013) Identification of Driver Genes in Hepatocellular Carcinoma by Exome Sequencing. Hepatology, 58 (5). pp. 1693-1702. ISSN 0270-9139

URL: http://www.ncbi.nlm.nih.gov/pubmed/23728943
DOI: 10.1002/hep.26540

Abstract

Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma (HCC). As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in HCC. We performed whole-exome sequencing on 87 HCCs and matched normal adjacent tissues to an average coverage of 59x. The overall mutation rate was roughly two mutations per Mb, with a median of 45 nonsynonymous mutations that altered the amino acid sequence (range, 2-381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%); CTNNB1 (10%); KEAP1 (8%); C16orf62 (8%); MLL4 (7%); and RAC2 (5%). Significantly affected gene families include the nucleotide-binding domain and leucine-rich repeat-containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family of methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Conclusion: The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of HCC. (Hepatology 2013;58:1693-1702)

Item Type: Paper
Uncontrolled Keywords: somatic mutations potential target genome cancer adenocarcinoma expression discovery framework pathways therapy
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
organs, tissues, organelles, cell types and functions > organs types and functions > liver
diseases & disorders > cancer > cancer types > liver cancer
diseases & disorders > cancer > cancer types
Investigative techniques and equipment > whole exome sequencing
Investigative techniques and equipment > assays > whole exome sequencing
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL labs > Powers lab
CSHL Cancer Center Shared Resources > Animal Services
Depositing User: Matt Covey
Date: November 2013
Date Deposited: 09 Dec 2013 17:08
Last Modified: 29 Oct 2015 16:39
PMCID: PMC3830584
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28896

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