@article{9b1b730f888f488c95e43c2b5d8776b5,
title = "Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts",
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.",
keywords = "Animals, DNA Copy Number Variations/genetics, Databases, Genetic, Gene Expression Regulation, Neoplastic, Humans, Mice, Neoplasm Metastasis, Polymorphism, Single Nucleotide/genetics, Whole Exome Sequencing, Xenograft Model Antitumor Assays",
author = "{PDXNET Consortium} and {EurOPDX Consortium} and Dennis Alferez-Castro and Katherine Spence and Robert Clarke and {et al.}",
note = "Funding Information: Support for the PDXNET consortium included funding provided by the National Institutes of Health (NIH) to the PDXNet Data Commons and Coordination Center (NCI U24-CA224067), the PDX Development and Trial Centers (NCI U54-CA224083, NCI U54-CA224070, NCI U54-CA224065, NCI U54-CA224076, NCI U54-CA233223 and NCI U54-CA233306) and the NCI Cancer Genomics Cloud (HHSN261201400008C and HHSN261201500003I). JAX PDX resource data were supported by the NCI of the NIH under the JAX Cancer Center NCI Grant (award number P30CA034196). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The genomic data for JAX PDX tumors used in this work were generated by JAX Genome Technologies and the Single Cell Biology Scientific Service. The development of PDX models and the generation of data from Seoul National University, in collaboration with JAX, was supported by the Korean Healthcare Technology R&D project through the Korean Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant number HI13C2148). C.L. is supported in part by operational funds from The First Affiliated Hospital of Xi{\textquoteright}an Jiaotong University. C.L. was a distinguished Ewha Womans University Professor, supported in part by the Ewha Womans University Research grant of 2018–2019. Sample procurement and next-generation sequencing at the Huntsman Cancer Institute were performed at the Genomics and Bioinformatics Analysis and Biorepository and Molecular Pathology shared resources, respectively, supported by NCI P30CA042014. SNP arrays were performed at the University of Utah Health Sciences Center Genomics Core. We are grateful to M. P. Klein for assistance with the SNP array data. M.H.B. is funded by the NIH under Ruth L. Kirschstein National Research Service Award Institutional Training Grant 5T32HG008962-05. M.T.L. is supported by a P30 Cancer Center Support Grant (CA125123) and a Core Facility Support Grant from the Cancer Research and Prevention Initiative of Texas (RP170691). PDX generation and WES at the University of Texas MD Anderson Cancer Center were supported by the University of Texas MD Anderson Cancer Center Moon Shots Program, funded by Specialized Program of Research Excellence grant CA-070907. J.A.R. is supported in part by the NIH/NCI through The University of Texas MD Anderson Cancer Center{\textquoteright}s Cancer Center Support Grant CA-016672—the Lung Program and Shared Core Facilities, the Specialized Program of Research Excellence grant CA-070907 and the Lung Cancer Moon Shot Program. The development of PDX models and the generation of data from The Wistar Institute was supported by the NCI, NIH (NCI R50-CA211199). Patient-Derived Models Repository data have been funded in whole or in part with federal funds from the NCI, NIH (contract number HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. The BRCA PDX models from Washington University used for this study were developed in part through support from the Breast Cancer Research Foundation and the Fashion Footwear Charitable Foundation of New York. The pancreatic cancer PDX models from Washington University used in this study were developed with the support of NCI grants P50 CA196510 and P30 CA091842 and The Foundation for Barnes-Jewish Hospital{\textquoteright}s Cancer Frontier Fund through the Siteman Cancer Center Investment Program. The data for these models were provided by U54-CA224083. Support for the EurOPDX consortium included funding provided by Fondazione AIRC under the 5 per Mille 2018 (ID. 21091) program (E. Medico, A.B. and L.T.), AIRC Investigator Grants 18532 (L.T.) and 20697 (A.B.), AIRC/CRUK/FC AECC Accelerator Award 22795 (L.T.), EU Horizon 2020 Research and Innovation Programme grant agreement number 731105 {\textquoteleft}EDIReX{\textquoteright} (E. Medico, A.B., L.T., A.T.B., V.S. and J.J.), Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per Mille Ministero della Salute 2015 (E. Medico and L.T.), 2014 and 2016 (L.T.), and 2017 (E. Medico), My First AIRC Grant 19047 (C.I.), EU Horizon 2020 Research and Innovation Programme grant agreement number 754923 {\textquoteleft}COLOSSUS{\textquoteright} (A.T.B., D.L. and L.T.), European Research Council Consolidator Grant 724748 {\textquoteleft}BEAT{\textquoteright} (A.B.), Science Foundation Ireland grant 13/CDA/2183 {\textquoteleft}COLOFORETELL{\textquoteright} (A.T.B.), Irish Health Research Board grant ILP-POR-2019-066 (A.T.B.), ISCIII Miguel Servet program CP14/00228 and the GHD-Pink/FERO Foundation grant (V.S.), Netherlands Organisation for Scientific Research (NWO) Vici grant 91814643 (J.J.), European Research Council Synergy project CombatCancer (J.J.), the Oncode Institute (J.J. and R.d.B.), the Dutch Cancer Society (J.J. and R.d.B.) and NCI grant U24 CA204781 (J.H.C. and T.F.M.). The EurOPDX consortium members thank C. Saura from the Breast Cancer and Melanoma Group (VHIO) and J. Balma{\~n}a from the Hereditary Cancer Genetics Group (VHIO) for providing study samples. We thank D. Krupke from JAX for assistance with organizing the tumor type information. Funding Information: A.L.W. and B.E.W. receive a portion of royalties if the University of Utah licenses certain PDX models to for-profit entities. M.T.L. is a founder of, and equity stake holder in, Tvardi Therapeutics, a founder of, and limited partner in, StemMed and a manager in StemMed Holdings. He also receives a portion of royalties if the Baylor College of Medicine licenses certain PDX models to for-profit entities. J.A.R. serves as a consultant and received stocks from Genprex, and receives royalties from patents issued. F.M.-B. reports receiving commercial research grants from Novartis, AstraZeneca, Calithera, Aileron, Bayer, Jounce, CytomX, eFFECTOR, Zymeworks, PUMA Biotechnology, Curis, Millennium, Daiichi Sankyo, Abbvie, Guardant Health, Takeda, Seattle Genetics and GlaxoSmithKline, as well as grants and travel-related fees from Taiho, Genentech, Debiopharm Group and Pfizer. She also served as a consultant to Pieris, Dialectica, Sumitomo Dainippon, Samsung Bioepis, Aduro, OrigiMed, Xencor, The Jackson Laboratory, Zymeworks, Kolon Life Science and Parexel International, and an advisor to Inflection Biosciences, GRAIL, DarwinHealth, Spectrum, Mersana and Seattle Genetics. L.T. reports receiving research grants from Symphogen, Servier, Pfizer and Merus, and he is in the speakers{\textquoteright} bureau of Eli Lilly, AstraZeneca and Merck. J.J. reports receiving funding for collaborative research from Artios Pharma. He also serves as a Scientific Advisory Board member of Artios Pharma. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = jan,
day = "7",
doi = "10.1038/s41588-020-00750-6",
language = "English",
volume = "53",
pages = "86--99",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Springer Nature",
number = "1",
}
