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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.

Original publication

DOI

10.1038/s41467-024-47547-3

Type

Journal article

Journal

Nature communications

Publication Date

05/2024

Volume

15

Addresses

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. rob.hynds@ucl.ac.uk.

Keywords

TRACERx consortium, Animals, Mice, Inbred NOD, Humans, Mice, Mice, SCID, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Disease Models, Animal, Xenograft Model Antitumor Assays, Genomics, Genetic Heterogeneity, Aged, Middle Aged, Female, Male, Heterografts, Exome Sequencing