[PDF][PDF] Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts

S Li, D Shen, J Shao, R Crowder, W Liu, A Prat, X He… - Cell reports, 2013 - cell.com
S Li, D Shen, J Shao, R Crowder, W Liu, A Prat, X He, S Liu, J Hoog, C Lu, L Ding, OL Griffith
Cell reports, 2013cell.com
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 …
Summary
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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