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

• DOI: 10.1016/j.celrep.2013.08.022
• Publication Date: 2013-09-19T18:06:17Z
• Authors: 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 Tao; Rodrigo Goncalves; Christopher Schlo...; 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 B. Mills; Ana Gonzalez-Angulo; John R. Edwards; Christopher Maher; Charles M. Perou; Elaine R. Mardis; Matthew J. Ellis
• Keywords: Estrogen receptor alpha; Fulvestrant; Gene dosage; Genome-wide Association Study

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 high fidelity. However, at single-nucleotide level, variable numbers PDX-specific somatic events documented, although they only rarely functionally significant. Variant allele frequencies often preserved in PDXs, demonstrating that clonal representation can transplantable. Estrogen-receptor-positive PDXs associated ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These produced different endocrine-therapy-response phenotypes human, cell line, PDX endocrine-response studies. Hence, deeply sequenced models are important resource search genome-forward treatment options capture endocrine-drug-resistance etiologies not observed standard lines. The tumor genome provides a benchmark assessing genetic drift after transplantation.