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

• Published in: Cell reports (Cambridge) Vol. 4; no. 6; pp. 1116 - 1130
• Main Authors: Li, Shunqiang, Shen, Dong, Shao, Jieya, Crowder, Robert, Liu, Wenbin, Prat, Aleix, He, Xiaping, Liu, Shuying, Hoog, Jeremy, Lu, Charles, Ding, Li, Griffith, Obi L., Miller, Christopher, Larson, Dave, Fulton, Robert S., Harrison, Michelle, Mooney, Tom, McMichael, Joshua F., Luo, Jingqin, Tao, Yu, Goncalves, Rodrigo, Schlosberg, Christopher, Hiken, Jeffrey F., Saied, Laila, Sanchez, Cesar, Giuntoli, Therese, Bumb, Caroline, Cooper, Crystal, Kitchens, Robert T., Lin, Austin, Phommaly, Chanpheng, Davies, Sherri R., Zhang, Jin, Kavuri, Megha Shyam, McEachern, Donna, Dong, Yi Yu, Ma, Cynthia, Pluard, Timothy, Naughton, Michael, Bose, Ron, Suresh, Rama, McDowell, Reida, Michel, Loren, Aft, Rebecca, Gillanders, William, DeSchryver, Katherine, Wilson, Richard K., Wang, Shaomeng, Mills, Gordon B., Gonzalez-Angulo, Ana, Edwards, John R., Maher, Christopher, Perou, Charles M., Mardis, Elaine R., Ellis, Matthew J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.09.2013; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Alleles; Animals; Biologia molecular; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Case studies; Càncer de mama; Drug Resistance, Neoplasm; Estradiol - pharmacology; Estrogen Receptor alpha - genetics; Estudi de casos; Female; Gene Amplification; Genomic Instability; Genomics; Genòmica; Heterografts; Humans; Mice; Molecular biology; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Staging; Phosphoproteins - genetics; Point Mutation; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Transcription Factors; Translocation, Genetic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.08.022

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. [Display omitted] •Genome-wide structural variants are highly preserved in breast cancer PDX models•PDXs harbor rarely functionally significant single-nucleotide variants•PDXs harbor ESR1 mutations and translocations associated with endocrine therapy resistance•ESR1 gene amplification in PDX correlated with paradoxical estradiol-induced regression In this study, Ellis and colleagues compare whole-tumor genomes from drug-resistant breast cancers with paired xenografts. Genomic fidelity upon transplantation was high for structural variants but variable at the single-nucleotide level. Therefore, tumor and xenograft whole-genome comparisons critically assess genetic drift and clonal representation. Additional analysis revealed ESR1 mutations, amplification, and translocations associated with endocrine resistance in lumenal xenografts. Sequenced patient-derived xenografts are an important resource for functional genomics and capture treatment-resistance etiologies that are not observed in standard cell lines.