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

Shunqiang Li, Dong Shen, Jieya Shao, Robert Crowder, Wenbin Liu, Aleix Prat, Xiaping He, Shuying Liu, Jeremy Hoog, Charles Lu, Li Ding, Obi L. Griffith, Christopher Miller, Dave Larson, Robert S. Fulton, Michelle Harrison, Tom Mooney, Joshua F. McMichael, Jingqin Luo, Yu TaoRodrigo Goncalves, Christopher Schlosberg, Jeffrey F. Hiken, Laila Saied, Cesar Sanchez, Therese Giuntoli, Caroline Bumb, Crystal Cooper, Robert T. Kitchens, Austin Lin, Chanpheng Phommaly, Sherri R. Davies, Jin Zhang, Megha Shyam Kavuri, Donna McEachern, Yi Yu Dong, Cynthia Ma, Timothy Pluard, Michael Naughton, Ron Bose, Rama Suresh, Reida McDowell, Loren Michel, Rebecca Aft, William Gillanders, Katherine DeSchryver, Richard K. Wilson, Shaomeng Wang, Gordon Mills, Ana Gonzalez-Angulo, John R. Edwards, Christopher Maher, Charles M. Perou, Elaine R. Mardis, Matthew J. Ellis

Research output: Contribution to journalArticle

302 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)1116-1130
Number of pages15
JournalCell Reports
Volume4
Issue number6
DOIs
StatePublished - Sep 26 2013
Externally publishedYes

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Heterografts
Breast Neoplasms
Genes
Genome
Therapeutics
Cells
Genetic Drift
Benchmarking
Cell Line
Gene Amplification
Aberrations
Drug Resistance
Gene Frequency
Estrogen Receptors
Tumors
Nucleotides
Transplantation
Ligands
Phenotype
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts. / Li, Shunqiang; Shen, Dong; Shao, Jieya; Crowder, Robert; Liu, Wenbin; Prat, Aleix; He, Xiaping; Liu, Shuying; Hoog, Jeremy; Lu, Charles; Ding, Li; Griffith, Obi L.; Miller, Christopher; Larson, Dave; Fulton, Robert S.; Harrison, Michelle; Mooney, Tom; McMichael, Joshua F.; Luo, Jingqin; Tao, Yu; Goncalves, Rodrigo; Schlosberg, Christopher; Hiken, Jeffrey F.; Saied, Laila; Sanchez, Cesar; Giuntoli, Therese; Bumb, Caroline; Cooper, Crystal; Kitchens, Robert T.; Lin, Austin; Phommaly, Chanpheng; Davies, Sherri R.; Zhang, Jin; Kavuri, Megha Shyam; McEachern, Donna; Dong, Yi Yu; Ma, Cynthia; Pluard, Timothy; Naughton, Michael; Bose, Ron; Suresh, Rama; McDowell, Reida; Michel, Loren; Aft, Rebecca; Gillanders, William; DeSchryver, Katherine; Wilson, Richard K.; Wang, Shaomeng; Mills, Gordon; Gonzalez-Angulo, Ana; Edwards, John R.; Maher, Christopher; Perou, Charles M.; Mardis, Elaine R.; Ellis, Matthew J.

In: Cell Reports, Vol. 4, No. 6, 26.09.2013, p. 1116-1130.

Research output: Contribution to journalArticle

Li, S, Shen, D, Shao, J, Crowder, R, Liu, W, Prat, A, He, X, Liu, S, Hoog, J, Lu, C, Ding, L, Griffith, OL, Miller, C, Larson, D, Fulton, RS, Harrison, M, Mooney, T, McMichael, JF, Luo, J, Tao, Y, Goncalves, R, Schlosberg, C, Hiken, JF, Saied, L, Sanchez, C, Giuntoli, T, Bumb, C, Cooper, C, Kitchens, RT, Lin, A, Phommaly, C, Davies, SR, Zhang, J, Kavuri, MS, McEachern, D, Dong, YY, Ma, C, Pluard, T, Naughton, M, Bose, R, Suresh, R, McDowell, R, Michel, L, Aft, R, Gillanders, W, DeSchryver, K, Wilson, RK, Wang, S, Mills, G, Gonzalez-Angulo, A, Edwards, JR, Maher, C, Perou, CM, Mardis, ER & Ellis, MJ 2013, 'Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts', Cell Reports, vol. 4, no. 6, pp. 1116-1130. https://doi.org/10.1016/j.celrep.2013.08.022
Li, Shunqiang ; Shen, Dong ; Shao, Jieya ; Crowder, Robert ; Liu, Wenbin ; Prat, Aleix ; He, Xiaping ; Liu, Shuying ; Hoog, Jeremy ; Lu, Charles ; Ding, Li ; Griffith, Obi L. ; Miller, Christopher ; Larson, Dave ; Fulton, Robert S. ; Harrison, Michelle ; Mooney, Tom ; McMichael, Joshua F. ; Luo, Jingqin ; Tao, Yu ; Goncalves, Rodrigo ; Schlosberg, Christopher ; Hiken, Jeffrey F. ; Saied, Laila ; Sanchez, Cesar ; Giuntoli, Therese ; Bumb, Caroline ; Cooper, Crystal ; Kitchens, Robert T. ; Lin, Austin ; Phommaly, Chanpheng ; Davies, Sherri R. ; Zhang, Jin ; Kavuri, Megha Shyam ; McEachern, Donna ; Dong, Yi Yu ; Ma, Cynthia ; Pluard, Timothy ; Naughton, Michael ; Bose, Ron ; Suresh, Rama ; McDowell, Reida ; Michel, Loren ; Aft, Rebecca ; Gillanders, William ; DeSchryver, Katherine ; Wilson, Richard K. ; Wang, Shaomeng ; Mills, Gordon ; Gonzalez-Angulo, Ana ; Edwards, John R. ; Maher, Christopher ; Perou, Charles M. ; Mardis, Elaine R. ; Ellis, Matthew J. / Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts. In: Cell Reports. 2013 ; Vol. 4, No. 6. pp. 1116-1130.
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title = "Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts",
abstract = "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",
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AU - Shen, Dong

AU - Shao, Jieya

AU - Crowder, Robert

AU - Liu, Wenbin

AU - Prat, Aleix

AU - He, Xiaping

AU - Liu, Shuying

AU - Hoog, Jeremy

AU - Lu, Charles

AU - Ding, Li

AU - Griffith, Obi L.

AU - Miller, Christopher

AU - Larson, Dave

AU - Fulton, Robert S.

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AU - McMichael, Joshua F.

AU - Luo, Jingqin

AU - Tao, Yu

AU - Goncalves, Rodrigo

AU - Schlosberg, Christopher

AU - Hiken, Jeffrey F.

AU - Saied, Laila

AU - Sanchez, Cesar

AU - Giuntoli, Therese

AU - Bumb, Caroline

AU - Cooper, Crystal

AU - Kitchens, Robert T.

AU - Lin, Austin

AU - Phommaly, Chanpheng

AU - Davies, Sherri R.

AU - Zhang, Jin

AU - Kavuri, Megha Shyam

AU - McEachern, Donna

AU - Dong, Yi Yu

AU - Ma, Cynthia

AU - Pluard, Timothy

AU - Naughton, Michael

AU - Bose, Ron

AU - Suresh, Rama

AU - McDowell, Reida

AU - Michel, Loren

AU - Aft, Rebecca

AU - Gillanders, William

AU - DeSchryver, Katherine

AU - Wilson, Richard K.

AU - Wang, Shaomeng

AU - Mills, Gordon

AU - Gonzalez-Angulo, Ana

AU - Edwards, John R.

AU - Maher, Christopher

AU - Perou, Charles M.

AU - Mardis, Elaine R.

AU - Ellis, Matthew J.

PY - 2013/9/26

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N2 - 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

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