Wu Xudong, Li Guohui
Laboratory of Molecular Modeling and Design, State key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Rd., Dalian 116023, PR China.
PLoS One. 2016 Aug 11;11(8):e0160463. doi: 10.1371/journal.pone.0160463. eCollection 2016.
Cancer is characterized by uncontrolled cell growth, and the cause of different cancers is generally attributed to checkpoint dysregulation of cell proliferation and apoptosis. Recent studies have shown that non-optimal codons were preferentially adopted by genes to generate cell cycle-dependent oscillations in protein levels. This raises the intriguing question of how dynamic changes of codon usage modulate the cancer genome to cope with a non-controlled proliferative cell cycle. In this study, we comprehensively analyzed the somatic mutations of codons in human cancers, and found that non-optimal codons tended to be accumulated through both synonymous and non-synonymous mutations compared with other types of genomic substitution. We further demonstrated that non-optimal codons were prevalently accumulated across different types of cancers, amino acids, and chromosomes, and genes with accumulation of non-optimal codons tended to be involved in protein interaction/signaling networks and encoded important enzymes in metabolic networks that played roles in cancer-related pathways. This study provides insights into the dynamics of codons in the cancer genome and demonstrates that accumulation of non-optimal codons may be an adaptive strategy for cancerous cells to win the competition with normal cells. This deeper interpretation of the patterns and the functional characterization of somatic mutations of codons will help to broaden the current understanding of the molecular basis of cancers.
癌症的特征是细胞生长不受控制，不同癌症的病因通常归因于细胞增殖和凋亡的检查点失调。最近的研究表明，基因优先采用非最优密码子来产生蛋白质水平的细胞周期依赖性振荡。这就提出了一个有趣的问题：密码子使用的动态变化如何调节癌症基因组以应对不受控制的增殖性细胞周期。在本研究中，我们全面分析了人类癌症中密码子的体细胞突变，发现与其他类型的基因组替代相比，非最优密码子倾向于通过同义突变和非同义突变积累。我们进一步证明，非最优密码子在不同类型的癌症、氨基酸和染色体中普遍积累，积累非最优密码子的基因倾向于参与蛋白质相互作用/信号网络，并编码代谢网络中在癌症相关途径中起作用的重要酶。这项研究为癌症基因组中密码子的动态变化提供了见解，并表明非最优密码子的积累可能是癌细胞与正常细胞竞争获胜的一种适应性策略。对密码子体细胞突变模式和功能特征的这种更深入解释将有助于拓宽目前对癌症分子基础的理解。
