Genome-wide transcriptional sequencing identifies novel mutations in metabolic genes in human hepatocellular carcinoma (HCC)

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Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer mortality in the world. Although the association of HCC with chronic liver disease is well established, the exact etiology of HCC remains undefined. Here, we report the results of next-generation transcriptome sequencing from three human hepatocellular carcinoma tumor/tumor-adjacent pairs. RNA sequencing was carried out using the Illumina Solexa Genome Analyzer generating approximately 240 million 75-mer reads for all six samples. Sequence reads were mapped to hg18 using BWA and Bambino, an in-house tool. Expression values were normalized with the RPKM method. We identified 4,513 up-regulated genes and 1,182 down-regulated genes in tumor compared to matched normal samples. This differential gene expression was further confirmed using a large data-set containing 434 normal liver and tumor samples. Network analysis of expression data identified the Aurora B signaling, FOXM1 transcription factor network and Wnt signaling pathways as altered in HCC. Our mutation analysis revealed 30 mutations that were validated using Sanger sequencing. In addition to known driver mutations such as TP53 and CTNNB1, our mutation analysis also identified six non-synonymous mutations in genes implicated in metabolic processes. Furthermore, five of these mutated genes are known to be involved in metabolic diseases such as diabetes and obesity: IRS1, HMGCS1, ATP8B1, PRMT6 and CLU. The data presented here strongly suggest that alteration of metabolic genes is highly associated with the development and progression of liver cancer and will provide further insight into etiology liver cancer

Acknowledgments

Meerzaman, Daoud; Yan, Chunhua; Edmonson, Michael; Schaefer, Carl; Chen, Qingrong; Clifford, Robert; Dunn, Barbara; Dong, Li; Finney, Richard; Cultraro, Constance; Hu, Ying; Yang, Zhihui; Nguyen, Cu; Kelley, Jenny; Cai, Shuang; Zhang, Hongen; Zhang, Jinghui; Wilson, Rebecca; Messmer, Lauren; Chung, Young-Hwa; Kim, Jeong; Park, Neung Hwa; Lyu, Myung-Soo; Song, Il Han; Buetow, Kenneth

Cite this work

Researchers should cite this work as follows:

  • (2014), "Genome-wide transcriptional sequencing identifies novel mutations in metabolic genes in human hepatocellular carcinoma (HCC)," https://ncihub.org/resources/81.

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Submitter

Cu Nguyen

NCI/CBIIT/CGR

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