Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.
Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.
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DOI：
10.1038/nm.3984
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发表时间：
2016-01
期刊：
影响因子：
82.9
通讯作者：
Maley CC
中科院分区：
文献类型：
--
作者：
Andor N;Graham TA;Jansen M;Xia LC;Aktipis CA;Petritsch C;Ji HP;Maley CC
肿瘤内异质性（ITH）驱动肿瘤进展和治疗耐药性。我们使用EXPANDS和PyClone检测来自TCGA肿瘤的1，165个外显子组序列中>10%频率的克隆。在12种癌症类型中，86%的肿瘤至少有两个克隆。细胞核形态学上的ITH与遗传性ITH相关（斯皮尔曼ρ：0.24-0.41，P<0.001）。通常出现在较小克隆中的驱动基因突变是生存风险因素（HR=2.15，95% CI：1.71-2.69）。当>2个克隆共存时，死亡风险也会增加（HR=1.49，95%CI：1.20-1.87）。在两个独立的数据集中，影响<25% or >75%肿瘤基因组的拷贝数改变预测风险降低（HR=0.15，95%CI：0.08-0.29）。当样本中同时存在四个以上的克隆时，死亡风险也会下降，这表明基因组不稳定性的成本和收益之间存在权衡。ITH和基因组不稳定性有可能成为普遍适用于癌症的有用措施。
Intra-tumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used EXPANDS and PyClone to detect clones >10% frequency within 1,165 exome sequences from TCGA tumors. 86% of tumors across 12 cancer types had at least two clones. ITH in nuclei morphology was associated with genetic ITH (Spearman ρ: 0.24–0.41, P<0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (HR=2.15, 95% CI: 1.71–2.69). The risk of mortality also increased when >2 clones coexisted (HR=1.49, 95% CI: 1.20–1.87). In two independent datasets, copy number alterations affecting either <25% or >75% of a tumor’s genome predicted reduced risk (HR=0.15, 95% CI: 0.08–0.29). Mortality risk also declined when more than four clones coexisted in the sample, suggesting a tradeoff between costs and benefits of genomic instability. ITH and genomic instability have the potential to be useful measures universally applicable across cancers.