Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, People's Republic of China.
Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12042-7. doi: 10.1073/pnas.1108715108. Epub 2011 Jul 5.
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.
我们展示了一例肝细胞癌肿瘤演变的分析。该病例对于癌症生长动力学和潜在的驱动突变提供了特别有价值的信息。我们从三个肿瘤中选取了九个不同的切片，以及从相邻的非肿瘤组织中选取了七个切片。对选定的切片进行了外显子和全基因组测序。然后在所有 9 个肿瘤和 7 个非肿瘤切片中分别验证了推定的体细胞突变。在验证的突变中，有 24 个是氨基酸变化；此外，还检测到 22 个大的插入缺失/拷贝数变异（>1 Mb）。这些体细胞突变在肿瘤细胞中定义了四个进化谱系。这些谱系的分离和扩张是最近发生的，且迅速，每个谱系显然只有一个谱系特异性的蛋白编码突变。因此，通过使用细胞群体遗传定义，本研究方法确定了三个编码改变（CCNG1、P62 和一个插入缺失/融合基因）为肿瘤驱动突变。这三个突变影响细胞周期控制和细胞凋亡，与早期积累的突变在功能上不同，其中许多突变涉及炎症/免疫或细胞锚定。不同阶段突变的不同功能可能反映了肿瘤生长背后的遗传相互作用。
