Bakhoum Samuel F, Landau Dan Avi
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065.
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065.
Cold Spring Harb Perspect Med. 2017 Jun 1;7(6):a029611. doi: 10.1101/cshperspect.a029611.
Large-scale, massively parallel sequencing of human cancer samples has revealed tremendous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse subpopulations-subclones-that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preserving favorable genotypes, a dependence that can be exploited for a therapeutic benefit. We discuss how whole-genome doubling events accelerate clonal evolution in a subset of tumors by providing a viable path toward favorable near-triploid karyotypes and present evidence for CIN-induced clonal speciation that can overcome the dependence on truncal initiating events.
对人类癌症样本进行的大规模、大规模平行测序揭示了单个肿瘤内部存在巨大的基因异质性。实际上，肿瘤是由不同亚群（亚克隆）混合而成的，这些亚群在空间和时间上各不相同。在这里，我们讨论癌症中克隆多样化的一个主要驱动因素，即染色体不稳定性（CIN），它补充了其他基因多样化模式，导致了人类癌症中常见的多层基因组不稳定性。癌细胞已经进化到微调染色体错分离率，以平衡异质性的获得，同时保留有利的基因型，这种依赖性可被用于治疗获益。我们讨论了全基因组加倍事件如何通过为形成有利的近三倍体核型提供一条可行途径，加速一部分肿瘤中的克隆进化，并提供了CIN诱导克隆物种形成的证据，这种克隆物种形成可以克服对主干起始事件的依赖。
