Kent David G, Green Anthony R
Wellcome Trust/MRC Stem Cell Institute, Hills Road, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
Department of Haematology, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
Cold Spring Harb Perspect Med. 2017 Apr 3;7(4):a027060. doi: 10.1101/cshperspect.a027060.
Cancers evolve as a consequence of multiple somatic lesions, with competition between subclones and sequential subclonal evolution. Some driver mutations arise either early or late in the evolution of different individual tumors, suggesting that the final malignant properties of a subclone reflect the sum of mutations acquired rather than the order in which they arose. However, very little is known about the cellular consequences of altering the order in which mutations are acquired. Recent studies of human myeloproliferative neoplasms show that the order in which individual mutations are acquired has a dramatic impact on the cell biological and molecular properties of tumor-initiating cells. Differences in clinical presentation, complications, and response to targeted therapy were all observed and implicate mutation order as an important player in cancer biology. These observations represent the first demonstration that the order of mutation acquisition influences stem and progenitor cell behavior and clonal evolution in any cancer. Thus far, the impact of different mutation orders has only been studied in hematological malignancies, and analogous studies of solid cancers are now required.
癌症是多种体细胞损伤的结果，亚克隆之间存在竞争并发生连续的亚克隆进化。一些驱动突变在不同个体肿瘤的进化过程中出现得早或晚，这表明亚克隆的最终恶性特性反映的是所获得突变的总和，而非其出现的顺序。然而，对于改变突变获得顺序的细胞后果，我们知之甚少。最近对人类骨髓增殖性肿瘤的研究表明，个体突变获得的顺序对肿瘤起始细胞的细胞生物学和分子特性有巨大影响。在临床表现、并发症以及对靶向治疗的反应方面均观察到差异，这表明突变顺序在癌症生物学中起着重要作用。这些观察结果首次证明，突变获得顺序会影响任何癌症中的干细胞和祖细胞行为以及克隆进化。到目前为止，不同突变顺序的影响仅在血液系统恶性肿瘤中进行了研究，现在需要对实体癌进行类似研究。
