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

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-nucle... Full description

Main Author: Li, Shunqiang
Other Authors: Shen, Dong , Shao, Jieya , Crowder, Robert , Liu, Wenbin , Prat Aparicio, 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, Aaustin , Phommaly, Chanpheng , Davies, Sherri R. , Zhang, Jim , Kavuri, Megha Shyam , Mceachern, Donna , Dong, Yi Yu , Ma, Cynthia , Pluard, Timothy , Naughton, Michael , Bose, Ron
Format: Electronic Article Electronic Article
Language: English
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Quelle: Universitat de Barcelona
ID: ISSN: 2211-1247
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recordid: barcelona2445/102127
title: Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts
format: Article
creator:
  • Li, Shunqiang
  • Shen, Dong
  • Shao, Jieya
  • Crowder, Robert
  • Liu, Wenbin
  • Prat Aparicio, 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, Aaustin
  • Phommaly, Chanpheng
  • Davies, Sherri R.
  • Zhang, Jim
  • Kavuri, Megha Shyam
  • Mceachern, Donna
  • Dong, Yi Yu
  • Ma, Cynthia
  • Pluard, Timothy
  • Naughton, Michael
  • Bose, Ron
subjects:
  • Càncer De Mama
  • Genòmica
  • Biologia Molecular
  • Estudi De Casos
  • Breast Cancer
  • Genomics
  • Molecular Biology
  • Case Studies
ispartof:
description: 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.
language: eng
source: Universitat de Barcelona
identifier: ISSN: 2211-1247
fulltext: fulltext_linktorsrc
issn:
  • 22111247
  • 2211-1247
url: Link


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titleEndocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts
creatorLi, Shunqiang ; Shen, Dong ; Shao, Jieya ; Crowder, Robert ; Liu, Wenbin ; Prat Aparicio, 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, Aaustin ; Phommaly, Chanpheng ; Davies, Sherri R. ; Zhang, Jim ; Kavuri, Megha Shyam ; Mceachern, Donna ; Dong, Yi Yu ; Ma, Cynthia ; Pluard, Timothy ; Naughton, Michael ; Bose, Ron
identifier ISSN: 2211-1247
subjectCàncer De Mama ; Genòmica ; Biologia Molecular ; Estudi De Casos ; Breast Cancer ; Genomics ; Molecular Biology ; Case Studies
descriptionTo 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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33Kavuri, Megha Shyam
34Mceachern, Donna
35Dong, Yi Yu
36Ma, Cynthia
37Pluard, Timothy
38Naughton, Michael
39Bose, Ron
titleEndocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts
descriptionTo 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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titleEndocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts
authorLi, Shunqiang ; Shen, Dong ; Shao, Jieya ; Crowder, Robert ; Liu, Wenbin ; Prat Aparicio, 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, Aaustin ; Phommaly, Chanpheng ; Davies, Sherri R. ; Zhang, Jim ; Kavuri, Megha Shyam ; Mceachern, Donna ; Dong, Yi Yu ; Ma, Cynthia ; Pluard, Timothy ; Naughton, Michael ; Bose, Ron
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6Molecular Biology
7Case Studies
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1Shen, Dong
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4Liu, Wenbin
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6He, Xiaping
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8Hoog, Jeremy
9Lu, Charles
10Ding, Li
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19Tao, Yu
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27Cooper, Crystal
28Kitchens, Robert T.
29Lin, Aaustin
30Phommaly, Chanpheng
31Davies, Sherri R.
32Zhang, Jim
33Kavuri, Megha Shyam
34Mceachern, Donna
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0Li, Shunqiang
1Shen, Dong
2Shao, Jieya
3Crowder, Robert
4Liu, Wenbin
5Prat Aparicio, Aleix
6He, Xiaping
7Liu, Shuying
8Hoog, Jeremy
9Lu, Charles
10Ding, Li
11Griffith, Obi L.
12Miller, Christopher
13Larson, Dave
14Fulton, Robert S.
15Harrison, Michelle
16Mooney, Tom
17Mcmichael, Joshua F.
18Luo, Jingqin
19Tao, Yu
20Goncalves, Rodrigo
21Schlosberg, Christopher
22Hiken, Jeffrey F.
23Saied, Laila
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25Giuntoli, Therese
26Bumb, Caroline
27Cooper, Crystal
28Kitchens, Robert T.
29Lin, Aaustin
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31Davies, Sherri R.
32Zhang, Jim
33Kavuri, Megha Shyam
34Mceachern, Donna
35Dong, Yi Yu
36Ma, Cynthia
37Pluard, Timothy
38Naughton, Michael
39Bose, Ron
atitleEndocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts
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abstractTo 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.
pubElsevier
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date2013-09-19