Journal
CELL REPORTS
Volume 4, Issue 6, Pages 1116-1130Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.08.022
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Funding
- Susan G. Komen for the Cure [BCTR0707808, KG090422, PG12220321]
- National Human Genome Research Institute [NHGRI U54 HG003079]
- NCI [3P50 CA68438, PO1CA099031, U54CA112970, KG081694, P30 CA16672]
- CTSA [UL1 RR024992]
- Breast Cancer Research Fund
- Barnes Jewish Hospital Foundation
- Theresa Harpole Foundation for Metastatic Breast Cancer
- TCGA Project [U24-CA143848]
- NCI Breast SPORE Program [P50-CA58223-09A1]
- Breast Cancer Research Foundation
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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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