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患者来源的异种移植瘤经历小鼠特异性肿瘤进化。

Patient-derived xenografts undergo mouse-specific tumor evolution.

作者信息

Ben-David Uri, Ha Gavin, Tseng Yuen-Yi, Greenwald Noah F, Oh Coyin, Shih Juliann, McFarland James M, Wong Bang, Boehm Jesse S, Beroukhim Rameen, Golub Todd R

机构信息

Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

出版信息

Nat Genet. 2017 Nov;49(11):1567-1575. doi: 10.1038/ng.3967. Epub 2017 Oct 9.

DOI:10.1038/ng.3967
PMID:28991255
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5659952/
Abstract

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 preexisting 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. Notably, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have major implications for PDX-based modeling of human cancer.

摘要

患者来源的异种移植瘤（PDXs）已成为一种重要的癌症模型系统，因为它们被认为能忠实地代表原发性肿瘤的基因组特征。在此，我们监测了24种癌症类型的1110个PDX样本中拷贝数改变（CNA）的动态变化。我们观察到在PDX传代过程中CNA迅速积累，这通常是由于对预先存在的小克隆的选择。PDX中CNA的获得与原发性肿瘤中观察到的非整倍体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不同。在原发性肿瘤中反复观察到的一些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繁殖过程中可能变得不再必要。值得注意的是，PDX的基因组稳定性与其对化疗和靶向药物的反应相关。这些发现对基于PDX的人类癌症建模具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/67071f74c383/nihms906208f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/262885685171/nihms906208f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/3a85f95df59a/nihms906208f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/0a9c3bc310ec/nihms906208f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/afd63a4917d9/nihms906208f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/a582a954a380/nihms906208f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/67071f74c383/nihms906208f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/262885685171/nihms906208f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/3a85f95df59a/nihms906208f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/0a9c3bc310ec/nihms906208f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/afd63a4917d9/nihms906208f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/a582a954a380/nihms906208f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d6d/5659952/67071f74c383/nihms906208f6.jpg

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