Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.
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DOI：
10.1056/nejmoa1113205
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发表时间：
2012-03-08
期刊：
影响因子：
--
通讯作者：
Swanton C
中科院分区：
文献类型：
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作者：
Gerlinger M;Rowan AJ;Horswell S;Math M;Larkin J;Endesfelder D;Gronroos E;Martinez P;Matthews N;Stewart A;Tarpey P;Varela I;Phillimore B;Begum S;McDonald NQ;Butler A;Jones D;Raine K;Latimer C;Santos CR;Nohadani M;Eklund AC;Spencer-Dene B;Clark G;Pickering L;Stamp G;Gore M;Szallasi Z;Downward J;Futreal PA;Swanton C
肿瘤内异质性可能促进肿瘤的演变和适应，并阻碍依赖于单个肿瘤活检样本结果的个性化医疗策略。为了检查肿瘤内的异质性，我们对原发性肾癌和相关转移部位的多个空间分离样本进行了外显子组测序、染色体畸变分析和倍性分析。我们使用免疫组化分析、突变功能分析和信使RNA表达谱来表征肿瘤内异质性的后果。系统发育重建显示肿瘤生长呈分支进化，所有体细胞突变中有63%至69%在每个肿瘤区域都无法检测到。在哺乳动物雷帕霉素靶蛋白（mTOR）激酶的自抑制结构域内观察到突变的瘤内异质性，与体内S6和4 EBP磷酸化和体外mTOR激酶活性的组成性激活相关。多个肿瘤抑制基因聚集在功能丧失上，观察到肿瘤内突变异质性;在单个肿瘤内，SETD 2、PTEN和KDM 5C经历了多个不同的和空间上分离的失活突变，表明聚集的表型进化。在同一肿瘤的不同区域检测到预后好和预后差的基因表达特征。等位基因组成和倍性分析揭示了广泛的肿瘤内异质性，26/30的肿瘤样本，从四个肿瘤窝藏不同的等位基因不平衡的配置文件和倍性异质性在两个四个肿瘤。肿瘤内异质性可能导致低估单个肿瘤活检样本描绘的肿瘤基因组学景观，并可能对个性化医学和生物标志物开发提出重大挑战。肿瘤内异质性，与异质性蛋白质功能，可能会促进肿瘤适应和治疗失败，通过达尔文选择。（由医学研究理事会和其他机构资助。）
Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)