Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts
Year: 2021
Type: article
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.
Source: Nature Genetics
Authors: 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 Mashl, Sherri 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, Funda Meric-Bernstam, Meenhard Herlyn, Michael A. Davies, Li Ding, Shunqiang Li, Ramaswamy Govindan, Claudio Isella, Jeffrey A. Moscow, Livio Trusolino, Annette T. Byrne, Jos Jonkers, Carol J. Bult, Enzo Medico, Jeffrey H. Chuang
Institutions: The Jackson Laboratory for Genomic Medicine, Candiolo Cancer Institute, University of Turin, Jackson Laboratory, The Netherlands Cancer Institute, Seoul National University, Frederick National Laboratory for Cancer Research, University of Utah, Huntsman Cancer Institute, The University of Texas MD Anderson Cancer Center, The Wistar Institute, Washington University in St. Louis, Seven Bridges Genomics (United States), Royal College of Surgeons in Ireland, VIB-KU Leuven Center for Cancer Biology, KU Leuven, Vall d'Hebron Institute of Oncology, Université Paris Sciences et Lettres, Institut Curie, Ewha Womans University, First Affiliated Hospital of Xi'an Jiaotong University, First Hospital of Xi'an, National Cancer Institute, Baylor College of Medicine, National Institutes of Health
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,390
Funders: U.S. Department of Health and Human Services, Breast Cancer Research Foundation, Eli Lilly and Company, Pfizer, AstraZeneca, Foundation for Barnes-Jewish Hospital, University of Utah, Huntsman Cancer Institute, Fashion Footwear Association of New York, Alvin J. Siteman Cancer Center, Cancer Research UK, National Centre for the Replacement, Refinement and Reduction of Animals in Research, Science Foundation Ireland, Seoul National University, Ewha Womans University, Ministero della Salute, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, KWF Kankerbestrijding, Associazione Italiana per la Ricerca sul Cancro, Servier, Symphogen, Fundación Fero, Oncode Institute, National Institutes of Health, University of Texas MD Anderson Cancer Center, Horizon 2020 Framework Programme, Instituto de Salud Carlos III, National Human Genome Research Institute, National Cancer Institute, H2020 European Research Council
Awards: G111615301, G1135378803, G1343352348, G1389837536, G1468253849, G1634253349, G1901027039, The functional interaction of EGFR and beta-catenin signalling in colorectal cancer: Genetics, mechanisms, and therapeutic potential., G2076520454, G2274722937, G2552051766, G278894908, G2831799598, Targeted Therapies in Melanoma, G2936846086, G3045601197, G3323679526, G3343343458, G3503792436, G351856440, G3804567512, The PDX Integrator- Re-purposing KOMP2 informatics to widely disseminate data from Patient Derived Xenografts, G386607036, G3962188502, G4132117823, G4258672507, G4585269469, Washington University SPORE in Pancreatic Cancer, G4935445674, G495187929, G5005492303, G5255084490, G5286278875, G531517939, G534868654, G5465708471, G556427208, G5888954722, G5894463464, G5920237370, G598389407, G6012682559, G6120206497, G61246291, G6336093431, G6393768786, G6717649131, G6736661663, G704564229, G7046174849, University of California Minority Patient-Derived Xenograft (PDX) Development and Trial Center (UCaMP) to Reduce Cancer Health Disparities, G7619975614, G76673548, G7756906289, G7868047788, ColoForetell: A Xenopatient Discovery Platform for the integrated Systems based Identification of Predictive Biomarkers for Targeted Therapies in Metastatic Colorectal Cancer, G7941272330, G8032570007, G8078730813, G8349780634, G8422249695, G8449251771, G8534818088, G8566719875, G858682239, G8594780166, G8824911526, G8858395165, G8882569155, G8971865872, G9000006824, G9000028008, G9000054324, G9000096706, G9000110418, G9000112290, G9000151111, G9000153296, G9000193521, G9000208361, G9000230064, G9000240210, G9000244278, G9000323711, G9000348607, Cancer Center Support Grant, Training Program in Genomic Medicine, PDXNet Data Commons and Coordinating Center, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, Consolidated Basic Cancer Research Program, Cancer Center Support Grant, G934622242, G995644284
OpenAlex ID: W3121069500