Identification of driver genes in hepatocellular carcinoma by exome sequencing

Cleary, S. P., Jeck, W. R., Zhao, X. B., 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. E., Guindi, M., Ghanekar, A., Chiang, D. Y. (April 2013) Identification of driver genes in hepatocellular carcinoma by exome sequencing. Cancer Research, 73 (8 (Sup). p. 4598. ISSN 0008-5472

URL: http://cancerres.aacrjournals.org/cgi/content/shor...
DOI: 10.1158/1538-7445.am2013-4598

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. As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in hepatocellular carcinoma. We performed whole exome sequencing on 87 hepatocellular carcinomas and matched normal adjacent tissues to an average coverage of 59x. The overall mutation rate was roughly 2.5 mutations per Mb, with a median of 45 non-synonymous mutations that altered the amino acid sequence (range 2 to 381). We found recurrent mutations in several genes with high transcript levels: TP53 (20%), CTNNB1 (15%), IGSF3 (9%) and KEAP1 (8%). 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. Clinical data demonstrated significantly decreased disease-free survival in tumors with p53 mutations (p=0.006) and a trend was observed towards higher rates of recurrence and shorter disease free survival among MLL mutation carriers. The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of hepatocellular carcinoma. The elucidation of genetic changes in HCC will enhance our understanding of hepatocarcinogenesis and influence disease prognosis and therapy.

Item Type: Paper
Additional Information: Meeting Abstract
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 > DNA, RNA structure, function, modification > genes, structure and function
diseases & disorders > cancer > cancer types > liver cancer
Publication Type > Meeting Abstract
Investigative techniques and equipment > whole exome sequencing
Investigative techniques and equipment > assays > whole exome sequencing
CSHL Authors:
Communities: CSHL labs > Powers lab
Depositing User: Matt Covey
Date: April 2013
Date Deposited: 11 Apr 2014 15:48
Last Modified: 21 Feb 2018 16:02
URI: http://repository.cshl.edu/id/eprint/29755

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