Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models.
Creators: name: Hynds, Robert E
name: Huebner, Ariana
name: Pearce, David R
name: Hill, Mark S
name: Akarca, Ayse U
name: Moore, David A
name: Ward, Sophia
name: Gowers, Kate HC
name: Karasaki, Takahiro
name: Al Bakir, Maise
name: Wilson, Gareth A
name: Pich, Oriol
name: Martínez-Ruiz, Carlos
name: Hossain, AS Md Mukarram
name: Pearce, Simon P
name: Sivakumar, Monica
name: Aissa, Assma Ben
name: Grönroos, Eva
name: Chandrasekharan, Deepak
name: Kolluri, Krishna K
name: Towns, Rebecca
name: Wang, Kaiwen
name: Cook, Daniel E
name: Bosshard-Carter, Leticia
name: Naceur-Lombardelli, Cristina
name: Rowan, Andrew J
name: Veeriah, Selvaraju
name: Litchfield, Kevin
name: Crosbie, Philip AJ
name: Dive, Caroline
name: Quezada, Sergio A
name: Janes, Sam M
name: Jamal-Hanjani, Mariam
name: Marafioti, Teresa
name: consortium, TRACERx
name: McGranahan, Nicholas
name: Swanton, Charles
Publisher: name: The Francis Crick Institute
Year: 2024
Subjects: classificationCode: Tumour Biology
subject: Tumour Biology
classificationCode: Stem Cells
subject: Stem Cells
classificationCode: Signalling & Oncogenes
subject: Signalling &amp; Oncogenes
classificationCode: Chemical Biology & High Throughput
subject: Chemical Biology &amp; High Throughput
classificationCode: Ecology,Evolution & Ethology
subject: Ecology,Evolution &amp; Ethology
classificationCode: Immunology
subject: Immunology
subject: FOS: Clinical medicine
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Computational & Systems Biology
subject: Computational &amp; Systems Biology
classificationCode: Genome Integrity & Repair
subject: Genome Integrity &amp; Repair
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Model organisms
subject: Model organisms
classificationCode: Cell Biology
subject: Cell Biology
classificationCode: Imaging
subject: Imaging
classificationCode: Cell Cycle & Chromosomes
subject: Cell Cycle &amp; Chromosomes

description: 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.