Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models
Robert E. Hynds, Ariana Huebner, David R. Pearce, Mark S. Hill, Ayse U. Akarca, David A. Moore, Sophia Ward, Kate H.C. Gowers, Takahiro Karasaki, Maise Al Bakir, Gareth A. Wilson, Oriol Pich, Carlos Martínez‐Ruiz, Arman Hossain, Simon P. Pearce, Monica Sivakumar, Assma Ben Aïssa, Eva Grönroos, Deepak P. Chandrasekharan, Krishna K. Kolluri, Rebecca Towns, Kaiwen Wang, Daniel E. Cook, Leticia Bosshard‐Carter, Cristina Naceur‐Lombardelli, Andrew J. Rowan, Selvaraju Veeriah, Kevin Litchfield, Philip Crosbie, Caroline Dive, Sergio A. Quezada, Sam M. Janes, Mariam Jamal‐Hanjani, Teresa Marafioti, Maise Al Bakir, J.F. Lester, Amrita Bajaj, Apostolos Nakas, Azmina Sodha-Ramdeen, Mohamad Tufail, Molly Scotland, Rebecca Boyles, Sridhar Rathinam, Claire Wilson, Domenic Marrone, Sean Dulloo, Dean A. Fennell, Gurdeep Matharu, Jacqui Shaw, Ekaterini Boleti, Heather Cheyne, Mohammed S. Khalil, Shirley Richardson, Tracey Cruickshank, Gillian Price, Keith M. Kerr, Sarah Benafif, Jack French, Kayleigh Gilbert, Babu Naidu, Akshay J. Patel, Aya Osman, Carol Enstone, Gerald Langman, Helen Shackleford, Madava Djearaman, Salma Kadiri, Gary Middleton, Angela Leek, Jack Davies Hodgkinson, Nikki Totton, Ángeles Montero, Elaine Smith, Eustace Fontaine, Felice Granato, António Paiva‐Correia, Juliette Novasio, Kendadai Rammohan, Leena Dennis Joseph, Paul Bishop, Rajesh Shah, Stuart Moss, Vijay V. Joshi, Katherine D. Brown, Mathew Carter, Anshuman Chaturvedi, Pedro Oliveira, Colin R. Lindsay, Fiona Blackhall, Matthew Krebs, Yvonne Summers, Alexandra Clipson, Jonathan Tugwood, Alastair Kerr, Dominic G. Rothwell, Hugo J.W.L. Aerts, Roland F. Schwarz, Tom L. Kaufmann, Rachel Rosenthal, Peter Van Loo
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.