多区域测序揭示的肿瘤内异质性和分支进化。
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.
机构信息
Cancer Research UK London Research Institute (M. Gerlinger, A.J.R., S.H., D.E., E.G., P.M., N.M., A.S., B.P., S.B., N.Q.M., C.R.S., B.S.-D., G.C., G.S., J.D., C.S.), Royal Marsden Hospital Department of Medicine (J.L., M.N., L.P., G.S., M. Gore), Wellcome Trust Sanger Institute (P.T., I.V., A.B., D.J., K.R., C.L., P.A.F.), Barts Cancer Institute at the Barts and the London School of Medicine and Dentistry (M. Gerlinger), and the University College London Cancer Institute (C.S.) - all in London; the Technical University of Denmark, Lyngby (A.C.E., Z.S.); and Harvard Medical School, Boston (Z.S.). Address reprint requests to Dr. Swanton at the Cancer Research UK London Research Institute, Translational Cancer Therapeutics Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, United Kingdom, or at
出版信息
N Engl J Med. 2012 Mar 8;366(10):883-892. doi: 10.1056/NEJMoa1113205.
BACKGROUND
Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.).
背景
肿瘤内异质性可能促进肿瘤进化和适应，并阻碍依赖于单个肿瘤活检样本结果的个体化医疗策略。
方法
为了研究肿瘤内异质性，我们对原发肾细胞癌及其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。我们使用免疫组织化学分析、突变功能分析和信使 RNA 表达谱分析来描述肿瘤内异质性的后果。
结果
系统发育重建显示出分支进化的肿瘤生长，所有体细胞突变中有 63%到 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）激酶的自动抑制结构域内的一个突变中观察到肿瘤内异质性，与体内 S6 和 4EBP 磷酸化以及体外 mTOR 激酶活性的组成性激活相关。多个肿瘤抑制基因的突变肿瘤内异质性导致功能丧失；SET 域包含 2 蛋白（SETD2）、PTEN 和 KDM5C 在单个肿瘤内经历了多个不同的、空间分离的失活突变，提示趋同表型进化。在同一肿瘤的不同区域检测到预后良好和不良的基因表达特征。等位基因组成和倍性分析揭示了广泛的肿瘤内异质性，在来自四个肿瘤的 30 个肿瘤样本中的 26 个样本中存在不同的等位基因失衡谱，在两个肿瘤中的四个肿瘤中存在倍性异质性。
结论
肿瘤内异质性可能导致对单个肿瘤活检样本所描绘的肿瘤基因组景观的低估，并且可能对个体化医疗和生物标志物的发展构成重大挑战。与异质蛋白功能相关的肿瘤内异质性可能通过达尔文选择促进肿瘤适应和治疗失败。（由医学研究委员会等资助）。
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