Patient-derived xenografts undergo mouse-specific tumor evolution

被引：578

作者：

Ben-David, Uri ^{[1
]}

Ha, Gavin ^{[1
,2
]}

Tseng, Yuen-Yi ^{[1
]}

Greenwald, Noah F. ^{[1
,3
,4
]}

Oh, Coyin ^{[1
]}

Shih, Juliann ^{[1
,2
]}

McFarland, James M. ^{[1
]}

Wong, Bang ^{[1
]}

Boehm, Jesse S. ^{[1
]}

Beroukhim, Rameen ^{[1
,2
,3
,5
,6
]}

Golub, Todd R. ^{[1
,7
,8
,9
]}

机构：

[1] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA 02142 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA

[5] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[7] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[8] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

[9] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

NATURE GENETICS | 2017年 / 49卷 / 11期

基金：

美国国家卫生研究院;

关键词：

GENE-EXPRESSION; BREAST-CANCER; GENOMIC CHARACTERIZATION; COPY NUMBER; CHROMOSOMAL INSTABILITY; STEM-CELLS; MODELS; HETEROGENEITY; SIGNATURE; CHEMOTHERAPY;

D O I：

10.1038/ng.3967

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1567 / +

页数：12

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