Clonal status of actionable driver events and the timing of mutational processes in cancer evolution.
Clonal status of actionable driver events and the timing of mutational processes in cancer evolution.
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DOI：
10.1126/scitranslmed.aaa1408
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发表时间：
2015-04-15
影响因子：
17.1
通讯作者：
Swanton C
中科院分区：
文献类型：
--
作者：
McGranahan N;Favero F;de Bruin EC;Birkbak NJ;Szallasi Z;Swanton C
要改进药物研发和精准医疗策略，可能需要弄清楚在肿瘤细胞的全部还是部分中存在可采取行动的驱动基因突变。我们分析了九种癌症类型，以确定驱动事件的亚克隆频率，确定癌症进化过程中的突变时间，并识别亚克隆扩张的驱动因素。尽管已知驱动基因的突变通常发生在癌症进化的早期，但我们也发现了后来出现的亚克隆“可采取行动的”突变，包括BRAF(V600E)、IDH1(R132H)、PIK3CA(E545K)、EGFR(L858R)和KRAS(G12D)，这些突变可能会影响靶向治疗方法的疗效。在胶质母细胞瘤中，超过20%的IDH1突变以及在所有肿瘤类型中PI3K（磷脂酰肌醇3 - 激酶）- AKT - mTOR（雷帕霉素靶蛋白）信号轴相关基因中15%的突变是亚克隆性的。RAS - MEK（丝裂原活化蛋白激酶激酶）信号轴的突变比亚克隆PI3K - AKT - mTOR信号相关基因的突变可能性更小。对晚期突变的分析揭示了APOBEC介导的突变与亚克隆驱动突变的获得之间的联系，并发现了参与亚克隆扩张的假定癌症基因，包括CTNNA2和ATXN1。我们的研究结果提供了肿瘤内异质性背景下驱动事件的泛癌症普查，并揭示了不同癌症的肿瘤进化模式。亚克隆驱动突变的频繁出现表明，需要根据发现驱动基因的肿瘤细胞比例来对靶向治疗反应进行分层。
Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal “actionable” mutations, including BRAF(V600E), IDH1(R132H), PIK3CA(E545K), EGFR(L858R), and KRAS(G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K(phosphatidylinositol 3-kinase)–AKT–mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS–MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTORsignaling. Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1. Our results provide a pan-cancer census of driver events within the context of intratumor heterogeneity and reveal patterns of tumor evolution across cancers. The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.