TY - JOUR
T1 - Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts
AU - Li, Shunqiang
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.
AU - Harrison, Michelle
AU - Mooney, Tom
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 B.
AU - Gonzalez-Angulo, Ana
AU - Edwards, John R.
AU - Maher, Christopher
AU - Perou, Charles M.
AU - Mardis, Elaine R.
AU - Ellis, Matthew J.
N1 - Funding Information:
This work was funded by grants to M.J.E. by Susan G. Komen for the Cure (BCTR0707808, KG090422, and PG12220321). The DNA sequencing and analysis were performed by the Genome Institute at Washington University School of Medicine and supported by grants to R.K.W. from the National Human Genome Research Institute (NHGRI U54 HG003079). The Tissue Procurement Core was supported by NCI 3P50 CA68438. The HAMLET Core was supported by CTSA grant UL1 RR024992. M.J.E. is also supported as a Susan G. Komen Scholar and by the Breast Cancer Research Fund, the Barnes Jewish Hospital Foundation, the Theresa Harpole Foundation for Metastatic Breast Cancer, and a gift from the Mary Speak family. The RPPA analysis was supported by NCI grants PO1CA099031, U54CA112970, KG081694, and P30 CA16672 to G.M. The RNA-seq was supported by grants from the TCGA Project (U24-CA143848), the NCI Breast SPORE Program (P50-CA58223-09A1), and the Breast Cancer Research Foundation to C.M.P. M.J.E. and C.M.P. own shares and have leadership positions in Bioclassifier and University Genomics, which has licensing income from patents related to the ProSigna breast cancer intrinsic subtype test.
PY - 2013/9/26
Y1 - 2013/9/26
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
AB - 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
UR - http://www.scopus.com/inward/record.url?scp=84884559238&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2013.08.022
DO - 10.1016/j.celrep.2013.08.022
M3 - Article
C2 - 24055055
AN - SCOPUS:84884559238
SN - 2639-1856
VL - 4
SP - 1116
EP - 1130
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -