Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts

Xing Yi Woo, Jessica Giordano, Anuj Srivastava, Zi Ming Zhao, Michael W. Lloyd, Roebi de Bruijn, Yun Suhk Suh, Rajesh Patidar, Li Chen, Sandra Scherer, Matthew H. Bailey, Chieh Hsiang Yang, Emilio Cortes-Sanchez, Yuanxin Xi, Jing Wang, Jayamanna Wickramasinghe, Andrew V. Kossenkov, Vito W. Rebecca, Hua Sun, R. Jay MashlSherri R. Davies, Ryan Jeon, Christian Frech, Jelena Randjelovic, Jacqueline Rosains, Francesco Galimi, Andrea Bertotti, Adam Lafferty, Alice C. O’Farrell, Elodie Modave, Diether Lambrechts, Petra ter Brugge, Violeta Serra, Elisabetta Marangoni, Rania El Botty, Hyunsoo Kim, Jong Il Kim, Han Kwang Yang, Charles Lee, Dennis A. Dean, Brandi Davis-Dusenbery, Yvonne A. Evrard, James H. Doroshow, Alana L. Welm, Bryan E. Welm, Michael T. Lewis, Bingliang Fang, Jack A. Roth, Anna Golebiewska, Simone P. Niclou, PDXNET Consortium, EurOPDX Consortium

Research output: Contribution to journalArticleResearchpeer-review

41 Citations (Scopus)

Abstract

Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.

Original languageEnglish
Pages (from-to)86-99
Number of pages14
JournalNature Genetics
Volume53
Issue number1
DOIs
Publication statusPublished - Jan 2021

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