The patterns and dynamics of genomic instability in metastatic pancreatic cancer.
The patterns and dynamics of genomic instability in metastatic pancreatic cancer.
复制标题
作者：
胰腺癌是一种侵袭性恶性肿瘤，5年死亡率为97- 98%，通常是由于广泛的转移性疾病。先前的研究表明，这种疾病具有复杂的基因组结构，经常发生拷贝数变化和点突变，但基因组重排尚未详细描述。尽管转移的临床重要性，仍然有一些基本问题的克隆结构的转移性肿瘤，包括系统发生关系之间的转移，规模正在进行的平行演变的转移和原发性网站，以及如何肿瘤传播。在这里，我们利用DNA测序的进展来注释13例胰腺癌患者的基因组重排，并探讨转移之间的克隆关系。我们发现，胰腺癌获得重排端粒功能障碍和异常的细胞周期控制，即失调的G1-S期转换与完整的G2-M检查点。这些启动了癌症基因的扩增，主要发生在癌症发展的早期，而不是疾病的后期。基因组的不稳定性经常在肿瘤扩散后持续存在，导致不同转移灶之间持续、平行甚至趋同的演变。我们发现转移起始细胞之间存在遗传异质性的证据;接种转移可能需要超出原发性肿瘤所需的驱动突变;转移的系统发育树显示器官特异性分支。这些数据证明了癌症中遗传变异的丰富性，这是由基因组不稳定性和进化选择的串联力量所造成的。
Pancreatic cancer is an aggressive malignancy with 5-year mortality of 97–98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterised in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of on-going parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here, we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-S phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than later stages of disease. Genomic instability frequently persists after cancer dissemination, resulting in on-going, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells; seeding metastasis may require driver mutations beyond those required for primary tumours; and phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, hewn by the tandem forces of genomic instability and evolutionary selection.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
168.9
作者：
Klein, CA;Blankenstein, TJF;Riethmüller, G
通讯作者：
Riethmüller, G
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.6
作者：
Embuscado, EE;Laheru, D;Iacobuzio-Donahue, CA
通讯作者：
Iacobuzio-Donahue, CA
影响因子：
78.5
作者：
Klein, Christoph A.
通讯作者：
Klein, Christoph A.