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

Xing Yi Woo(Jackson Laboratory), Jessica Giordano(Candiolo Cancer Institute), Anuj Srivastava(Jackson Laboratory), Min Jin Ha(Jackson Laboratory), Michael W. Lloyd(Jackson Laboratory), Roebi de Bruijn(The Netherlands Cancer Institute), Yun‐Suhk Suh(Seoul National University), Rajesh Patidar(Frederick National Laboratory for Cancer Research), Li Chen(Frederick National Laboratory for Cancer Research), Sandra D. Scherer(University of Utah), Matthew H. Bailey(University of Utah), Chieh‐Hsiang Yang(University of Utah), Emilio Cortes-Sanchez(University of Utah), Yuanxin Xi(The University of Texas MD Anderson Cancer Center), Jing Wang(The University of Texas MD Anderson Cancer Center), Jayamanna Wickramasinghe(The Wistar Institute), Andrew V. Kossenkov(The Wistar Institute), Vito W. Rebecca(The Wistar Institute), Hua Sun(Washington University in St. Louis), R. Jay Mashl(Washington University in St. Louis), Sherri R. Davies(Washington University in St. Louis), Ryan Jeon(Seven Bridges Genomics (United States)), Christian Frech(Seven Bridges Genomics (United States)), Jelena Randjelović(Seven Bridges Genomics (United States)), Jacqueline Rosains(Seven Bridges Genomics (United States)), Francesco Galimi(Candiolo Cancer Institute), Andrea Bertotti(Candiolo Cancer Institute), Adam Lafferty(Royal College of Surgeons in Ireland), Alice C. O’Farrell(Royal College of Surgeons in Ireland), Elodie Modave(VIB-KU Leuven Center for Cancer Biology), Diether Lambrechts(VIB-KU Leuven Center for Cancer Biology), Petra ter Brugge(The Netherlands Cancer Institute), Violeta Serra(Vall d'Hebron Institute of Oncology), Elisabetta Marangoni(Université Paris Sciences et Lettres), Rania El Botty(Université Paris Sciences et Lettres), Hyunsoo Kim(Jackson Laboratory), Jong‐Il Kim(Seoul National University), Han‐Kwang Yang(Seoul National University), Charles Lee(Ewha Womans University), Dennis A. Dean(Seven Bridges Genomics (United States)), Brandi N. Davis‐Dusenbery(Seven Bridges Genomics (United States)), Yvonne A. Evrard(Frederick National Laboratory for Cancer Research), James H. Doroshow(National Cancer Institute), Alana L. Welm(University of Utah), Bryan E. Welm(University of Utah), Michael T. Lewis(Baylor College of Medicine), Bingliang Fang(The University of Texas MD Anderson Cancer Center), Jack A. Roth(The University of Texas MD Anderson Cancer Center), Funda Meric‐Bernstam(The University of Texas MD Anderson Cancer Center), Meenhard Herlyn(The Wistar Institute), Michael A. Davies(The University of Texas MD Anderson Cancer Center), Li Ding(Washington University in St. Louis), Shunqiang Li(Washington University in St. Louis), Ramaswamy Govindan(Washington University in St. Louis), Claudio Isella(Candiolo Cancer Institute), Jeffrey A. Moscow(National Cancer Institute), Livio Trusolino(Candiolo Cancer Institute), Annette T. Byrne(Royal College of Surgeons in Ireland), Jos Jonkers(The Netherlands Cancer Institute), Carol J. Bult(Jackson Laboratory), Enzo Médico(Candiolo Cancer Institute), Jeffrey H. Chuang(Jackson Laboratory)
Nature Genetics
January 1, 2021
10.1038/s41588-020-00750-6
Cited by 191Open Access
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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.

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