Patient-derived xenografts undergo mouse-specific tumor evolution.
Patient-derived xenografts undergo mouse-specific tumor evolution.
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DOI：
10.1038/ng.3967
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发表时间：
2017-11
期刊：
影响因子：
30.8
通讯作者：
Golub TR
中科院分区：
文献类型：
--
作者：
Ben-David U;Ha G;Tseng YY;Greenwald NF;Oh C;Shih J;McFarland JM;Wong B;Boehm JS;Beroukhim R;Golub TR
患者来源的异种移植物（PDX）已成为一种重要的癌症模型系统，因为它们被认为忠实地代表了原发性肿瘤的基因组特征。在这里，我们监测了 24 种癌症类型的 1,110 个 PDX 样本中拷贝数改变 (CNA) 的动态。我们观察到 CNA 在 PDX 传代过程中快速积累，这通常是由于选择了预先存在的小克隆。 PDX 中的 CNA 获取与原发性肿瘤中观察到的非整倍性和遗传异质性的组织特异性水平相关。然而，PDX 传代过程中获得的特定 CNA 与患者肿瘤进化过程中获得的 CNA 不同。在原发性肿瘤中反复观察到的几个 CNA 在 PDX 中逐渐消失，这表明在人类中经历正选择的事件在小鼠的繁殖过程中可能变得可有可无。重要的是，PDX 的基因组稳定性与其对化疗和靶向药物的反应相关。这些发现对于基于 PDX 的人类癌症建模具有重要意义。
Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of pre-existing minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Importantly, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have important implications for PDX-based modeling of human cancer.
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影响因子：
82.9
作者：
Gao, Hui;Korn, Joshua M.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
11.2
作者：
Birkbak NJ;Eklund AC;Li Q;McClelland SE;Endesfelder D;Tan P;Tan IB;Richardson AL;Szallasi Z;Swanton C
通讯作者：
Swanton C
影响因子：
8
作者：
Guenther, H. S.;Schmidt, N. O.;Lamszus, K.
通讯作者：
Lamszus, K.
影响因子：
30.8
作者：
Gibson WJ;Hoivik EA;Halle MK;Taylor-Weiner A;Cherniack AD;Berg A;Holst F;Zack TI;Werner HM;Staby KM;Rosenberg M;Stefansson IM;Kusonmano K;Chevalier A;Mauland KK;Trovik J;Krakstad C;Giannakis M;Hodis E;Woie K;Bjorge L;Vintermyr OK;Wala JA;Lawrence MS;Getz G;Carter SL;Beroukhim R;Salvesen HB
通讯作者：
Salvesen HB
影响因子：
82.9
作者：
Andor N;Graham TA;Jansen M;Xia LC;Aktipis CA;Petritsch C;Ji HP;Maley CC
通讯作者：
Maley CC