Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts

被引：493

作者：

Li, Shunqiang ^{[1
,2
]}

Shen, Dong ^{[3
]}

Shao, Jieya ^{[1
]}

Crowder, Robert ^{[1
]}

Liu, Wenbin ^{[4
]}

Prat, Aleix ^{[5
,6
,7
]}

He, Xiaping ^{[6
,7
]}

Liu, Shuying ^{[4
]}

Hoog, Jeremy ^{[1
]}

Lu, Charles ^{[3
]}

Ding, Li ^{[2
,3
,10
]}

Griffith, Obi L. ^{[3
]}

Miller, Christopher ^{[3
]}

Larson, Dave ^{[3
]}

Fulton, Robert S. ^{[3
]}

Harrison, Michelle ^{[3
]}

Mooney, Tom ^{[3
]}

McMichael, Joshua F. ^{[3
]}

Luo, Jingqin ^{[2
,8
]}

Tao, Yu ^{[8
]}

Goncalves, Rodrigo ^{[1
]}

Schlosberg, Christopher ^{[9
]}

Hiken, Jeffrey F. ^{[9
]}

Saied, Laila ^{[10
]}

Sanchez, Cesar ^{[11
]}

Giuntoli, Therese ^{[1
]}

Bumb, Caroline ^{[1
]}

Cooper, Crystal ^{[1
]}

Kitchens, Robert T. ^{[1
]}

Lin, Austin ^{[1
]}

Phommaly, Chanpheng ^{[1
]}

Davies, Sherri R. ^{[1
]}

Zhang, Jin ^{[3
]}

Kavuri, Megha Shyam ^{[1
]}

McEachern, Donna ^{[12
,13
,14
]}

Dong, Yi Yu ^{[1
]}

Ma, Cynthia ^{[1
,2
]}

Pluard, Timothy ^{[1
,2
]}

Naughton, Michael ^{[1
,2
]}

Bose, Ron ^{[1
,2
]}

Suresh, Rama ^{[1
]}

McDowell, Reida ^{[1
]}

Michel, Loren ^{[1
,2
]}

Aft, Rebecca ^{[15
]}

Gillanders, William ^{[15
]}

DeSchryver, Katherine ^{[1
]}

Wilson, Richard K. ^{[2
,3
]}

Wang, Shaomeng ^{[12
,13
,14
]}

Mills, Gordon B. ^{[4
]}

Gonzalez-Angulo, Ana ^{[4
]}

机构：

[1] Washington Univ, Div Oncol, Dept Internal Med, Sect Breast Oncol, St Louis, MO 63110 USA

[2] Washington Univ, Siteman Canc Ctr, Breast Canc Program, St Louis, MO 63110 USA

[3] Washington Univ, Genome Inst, St Louis, MO 63110 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[5] Vall dHebron Inst Oncol VHIO, Translat Genom Unit, Barcelona 08035, Spain

[6] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA

[7] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA

[8] Washington Univ, Dept Med, Div Biostat, St Louis, MO 63110 USA

[9] Washington Univ, Ctr Pharmacogen, St Louis, MO 63110 USA

[10] Washington Univ, Dept Internal Med, Residency Program, St Louis, MO 63110 USA

[11] Pontificia Univ Catolica Chile, Dept Hematol Oncol, Santiago 8330032, Chile

[12] Univ Michigan, Ctr Comprehens Canc, Dept Internal Med, Ann Arbor, MI 48109 USA

[13] Univ Michigan, Ctr Comprehens Canc, Dept Pharmacol, Ann Arbor, MI 48109 USA

[14] Univ Michigan, Ctr Comprehens Canc, Dept Med Chem, Ann Arbor, MI 48109 USA

[15] Washington Univ, Dept Surg, St Louis, MO 63110 USA

来源：

CELL REPORTS | 2013年 / 4卷 / 06期

关键词：

POSTMENOPAUSAL PATIENTS; INTRINSIC SUBTYPE; TUMOR; METASTASIS; INSTABILITY; ACTIVATION; MECHANISM; EVOLUTION; PATHWAY; TISSUE;

D O I：

10.1016/j.celrep.2013.08.022

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.

引用

页码：1116 / 1130

页数：15

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