Identification of driver genes in hepatocellular carcinoma by exome sequencing
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Open Access
- 31 May 2013
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 58 (5), 1693-1702
- https://doi.org/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 59×. 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)Keywords
Funding Information
- the National Institutes of Health (U24CA143845)
- The University Cancer Research Fund
- Alfred P. Sloan Research Fellowship
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