Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data

We present the analysis of the evolution of tumors in a case of hepatocellular carcinoma. This case is particularly informative about cancer growth dynamics and the underlying driving mutations. We sampled nine different sections from three tumors and seven more sections from the adjacent nontumor t...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 29; pp. 12042 - 12047
Main Authors:	Tao, Yong, Ruan, Jue, Yeh, Shiou-Hwei, Lu, Xuemei, Wang, Yu, Zhai, Weiwei, Cai, Jun, Ling, Shaoping, Gong, Qiang, Chong, Zecheng, Qu, Zhengzhong, Li, Qianqian, Liu, Jiang, Yang, Jin, Zheng, Caihong, Zeng, Changqing, Wang, Hurng-Yi, Zhang, Jing, Wang, Sheng-Han, Hao, Lingtong, Dong, Lili, Li, Wenjie, Sun, Min, Zou, Wei, Yu, Caixia, Li, Chaohua, Liu, Guojing, Jiang, Lan, Xu, Jin, Huang, Huanwei, Li, Chunyan, Mi, Shuangli, Zhang, Bing, Chen, Baoxian, Zhao, Wenming, Hu, Songnian, Zhuang, Shi-Mei, Shen, Yang, Shi, Suhua, Brown, Christopher, White, Kevin P, Chen, Ding-Shinn, Chen, Pei-Jer, Wu, Chung -I
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 19-07-2011 National Acad Sciences
Subjects:	Adult Amino acid sequence amino acids Apoptosis Apoptosis - genetics Biological Sciences Cancer Carcinoma, Hepatocellular - etiology Carcinoma, Hepatocellular - genetics Cell cycle Cell Cycle - genetics Cell growth Cell lines copy number Cyclin G1 - genetics Data processing Disease Progression DNA Mutational Analysis DNA Primers - genetics Evolution Evolution, Molecular Exons Female Fusion protein Gene Frequency gene fusion Genetic analysis Genetic mutation Genomes Genomics - methods Hepatitis B, Chronic - complications Hepatocellular carcinoma Hepatocytes hepatoma Humans Immunity INDEL Mutation - genetics Inflammation Kidney cells Liver Liver Neoplasms - etiology Liver Neoplasms - genetics Mutation neoplasm cells Point Mutation - genetics RNA-Binding Proteins - genetics sequence analysis Sequencing somatic mutation tissues Tumor cells Tumors Virus Integration - genetics
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Summary:	We present the analysis of the evolution of tumors in a case of hepatocellular carcinoma. This case is particularly informative about cancer growth dynamics and the underlying driving mutations. We sampled nine different sections from three tumors and seven more sections from the adjacent nontumor tissues. Selected sections were subjected to exon as well as whole-genome sequencing. Putative somatic mutations were then individually validated across all 9 tumor and 7 nontumor sections. Among the mutations validated, 24 were amino acid changes; in addition, 22 large indels/copy number variants (>1 Mb) were detected. These somatic mutations define four evolutionary lineages among tumor cells. Separate evolution and expansion of these lineages were recent and rapid, each apparently having only one lineage-specific protein-coding mutation. Hence, by using a cell-population genetic definition, this approach identified three coding changes (CCNG1, P62, and an indel/fusion gene) as tumor driver mutations. These three mutations, affecting cell cycle control and apoptosis, are functionally distinct from mutations that accumulated earlier, many of which are involved in inflammation/immunity or cell anchoring. These distinct functions of mutations at different stages may reflect the genetic interactions underlying tumor growth.
Bibliography:	http://dx.doi.org/10.1073/pnas.1108715108 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 1Y.T., J.R., S.-H.Y., X.L., Y.W., W. Z., and J.C. contributed equally to this work. Author contributions: S.-H.Y., X.L., D.-S.C., P.-J.C., and C.-I.W. designed research; Y.T., S.-H.Y., Q.G., Z.Q., J.Y., C. Zheng, H.-Y.W., S.-H.W., W.L., M.S., Chaohua Li, G.L., H.H., Chunyan Li, S.M., B.Z., B.C., S.-M.Z., and S.S. performed research; J.R., Y.W., W. Zhai, J.C., S.L., Q.G., Z.C., Q.L., J.Z., L.H., L.D., W. Zou, C.Y., L.J., J.X., W. Zhao, S.H., and Y.S. analyzed data; S.-H.Y. and P.-J.C. provided clinical samples; and Y.T., J.R., S.-H.Y., X.L., Y.W., W. Zhai, J.C., S.L., J.L., C. Zeng, C.B., K.P.W., D.-S.C., P.-J.C., and C.-I.W. wrote the paper. Contributed by Ding-Shinn Chen, June 3, 2011 (sent for review March 7, 2011)
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1108715108