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-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.
Section of Breast Oncology, Division of Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Siteman Cancer Center Breast Cancer Program, Washington University in St. Louis, St. Louis, MO 63110, USA.
Shunqiang
S
Li
Dong
D
Shen
Jieya
J
Shao
Robert
R
Crowder
Wenbin
W
Liu
Aleix
A
Prat
Xiaping
X
He
Shuying
S
Liu
Jeremy
J
Hoog
Charles
C
Lu
Li
L
Ding
Obi L
OL
Griffith
Christopher
C
Miller
Dave
D
Larson
Robert S
RS
Fulton
Michelle
M
Harrison
Tom
T
Mooney
Joshua F
JF
McMichael
Jingqin
J
Luo
Yu
Y
Tao
Rodrigo
R
Goncalves
Christopher
C
Schlosberg
Jeffrey F
JF
Hiken
Laila
L
Saied
Cesar
C
Sanchez
Therese
T
Giuntoli
Caroline
C
Bumb
Crystal
C
Cooper
Robert T
RT
Kitchens
Austin
A
Lin
Chanpheng
C
Phommaly
Sherri R
SR
Davies
Jin
J
Zhang
Megha Shyam
MS
Kavuri
Donna
D
McEachern
Yi Yu
YY
Dong
Cynthia
C
Ma
Timothy
T
Pluard
Michael
M
Naughton
Ron
R
Bose
Rama
R
Suresh
Reida
R
McDowell
Loren
L
Michel
Rebecca
R
Aft
William
W
Gillanders
Katherine
K
DeSchryver
Richard K
RK
Wilson
Shaomeng
S
Wang
Gordon B
GB
Mills
Ana
A
Gonzalez-Angulo
John R
JR
Edwards
Christopher
C
Maher
Charles M
CM
Perou
Elaine R
ER
Mardis
Matthew J
MJ
Ellis
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D042822:Genomic Instability; D064593:Heterografts; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009367:Neoplasm Staging; D010750:Phosphoproteins / Q000235:genetics; D017354:Point Mutation; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors; D014178:Translocation, Genetic; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D012334:RNA, Neoplasm; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D004958:Estradiol