title: Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data.
abstract: 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.
authors: Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, People's Republic of China.
authors: Yong
authors: Y
authors: Tao
authors: Jue
authors: J
authors: Ruan
authors: Shiou-Hwei
authors: SH
authors: Yeh
authors: Xuemei
authors: X
authors: Lu
authors: Yu
authors: Y
authors: Wang
authors: Weiwei
authors: W
authors: Zhai
authors: Jun
authors: J
authors: Cai
authors: Shaoping
authors: S
authors: Ling
authors: Qiang
authors: Q
authors: Gong
authors: Zecheng
authors: Z
authors: Chong
authors: Zhengzhong
authors: Z
authors: Qu
authors: Qianqian
authors: Q
authors: Li
authors: Jiang
authors: J
authors: Liu
authors: Jin
authors: J
authors: Yang
authors: Caihong
authors: C
authors: Zheng
authors: Changqing
authors: C
authors: Zeng
authors: Hurng-Yi
authors: HY
authors: Wang
authors: Jing
authors: J
authors: Zhang
authors: Sheng-Han
authors: SH
authors: Wang
authors: Lingtong
authors: L
authors: Hao
authors: Lili
authors: L
authors: Dong
authors: Wenjie
authors: W
authors: Li
authors: Min
authors: M
authors: Sun
authors: Wei
authors: W
authors: Zou
authors: Caixia
authors: C
authors: Yu
authors: Chaohua
authors: C
authors: Li
authors: Guojing
authors: G
authors: Liu
authors: Lan
authors: L
authors: Jiang
authors: Jin
authors: J
authors: Xu
authors: Huanwei
authors: H
authors: Huang
authors: Chunyan
authors: C
authors: Li
authors: Shuangli
authors: S
authors: Mi
authors: Bing
authors: B
authors: Zhang
authors: Baoxian
authors: B
authors: Chen
authors: Wenming
authors: W
authors: Zhao
authors: Songnian
authors: S
authors: Hu
authors: Shi-Mei
authors: SM
authors: Zhuang
authors: Yang
authors: Y
authors: Shen
authors: Suhua
authors: S
authors: Shi
authors: Christopher
authors: C
authors: Brown
authors: Kevin P
authors: KP
authors: White
authors: Ding-Shinn
authors: DS
authors: Chen
authors: Pei-Jer
authors: PJ
authors: Chen
authors: Chung-I
authors: CI
authors: Wu
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D056766:Cyclin G1 / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D018450:Disease Progression; D019143:Evolution, Molecular; D005260:Female; D005787:Gene Frequency; D023281:Genomics / Q000379:methods*; D019694:Hepatitis B, Chronic / Q000150:complications*; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D016662:Virus Integration / Q000235:genetics
chemical_list: C534702:CCNG1 protein, human; D056766:Cyclin G1; D017931:DNA Primers; C118585:P62 protein, human; D016601:RNA-Binding Proteins