Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models
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Rob Hynds Ariana Huebner David R Pearce Mark S Hill Ayse U Akarca David A Moore Sophie Ward Kate HC Gowers Takahiro Karasaki Maise Al Bakir Gareth Wilson Oriol Pich Carlos Martínez-Ruiz AS Md Mukarram Hossain Simon P Pearce Monica Sivakumar Assma Ben Aissa Eva Gronroos Deepak Chandrasekharan Krishna K Kolluri Rebecca Towns Kaiwen Wang Daniel E Cook Leticia Bosshard-Carter Cristina Naceur-Lombardelli Andrew Rowan Selvaraju Veeriah Kevin Litchfield Philip AJ Crosbie Caroline Dive Sergio A Quezada Sam M Janes Mariam Jamal-Hanjani Teresa Marafioti TRACERx consortium Nicholas McGranahan Charles Swanton
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Abstract
Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.
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Journal
Nature Communications
Volume
15
Issue number
1
Pages
4653
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10.1038/s41467-024-47547-3
Europe PubMed Central
38821942
Pubmed
38821942
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The publication was previously a preprint.
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