Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models
Authors: Hynds Robert E. , Huebner Ariana , Pearce David R. , Hill Mark S. , Akarca Ayse U. , Moore David A. , Ward Sophia , Gowers Kate H. C. , Karasaki Takahiro , Al Bakir Maise , Wilson Gareth A. , Pich Oriol , Martínez-Ruiz Carlos , Hossain A. S. Md Mukarram , Pearce Simon P. , Sivakumar Monica , Ben Aissa Assma , Grönroos Eva , Chandrasekharan Deepak , Kolluri Krishna K. , Towns Rebecca , Wang Kaiwen , Cook Daniel E. , Bosshard-Carter Leticia , Naceur-Lombardelli Cristina , Rowan Andrew J. , Veeriah Selvaraju , Litchfield Kevin , Crosbie Philip A. J. , Dive Caroline , Quezada Sergio A. , Janes Sam M. , Jamal-Hanjani Mariam , Marafioti Teresa ,   TRACERx consortium, Al Bakir Maise , Lester Jason F. , Bajaj Amrita , Nakas Apostolos , Sodha-Ramdeen Azmina , Tufail Mohamad , Scotland Molly , Boyles Rebecca , Rathinam Sridhar , Wilson Claire , Marrone Domenic , Dulloo Sean , Fennell Dean A. , Matharu Gurdeep , Shaw Jacqui A. , Boleti Ekaterini , Cheyne Heather , Khalil Mohammed , Richardson Shirley , Cruickshank Tracey , Price Gillian , Kerr Keith M. , Benafif Sarah , French Jack , Gilbert Kayleigh , Naidu Babu , Patel Akshay J. , Osman Aya , Enstone Carol , Langman Gerald , Shackleford Helen , Djearaman Madava , Kadiri Salma , Middleton Gary , Leek Angela , Hodgkinson Jack Davies , Totton Nicola , Montero Angeles , Smith Elaine , Fontaine Eustace , Granato Felice , Paiva-Correia Antonio , Novasio Juliette , Rammohan Kendadai , Joseph Leena , Bishop Paul , Shah Rajesh , Moss Stuart , Joshi Vijay , Brown Katherine D. , Carter Mathew , Chaturvedi Anshuman , Oliveira Pedro , Lindsay Colin R. , Blackhall Fiona H. , Krebs Matthew G. , Summers Yvonne , Clipson Alexandra , Tugwood Jonathan , Kerr Alastair , Rothwell Dominic G. , Aerts Hugo J. W. L. , Schwarz Roland F. , Kaufmann Tom L. , Rosenthal Rachel , Van Loo Peter , Birkbak Nicolai J. , Szallasi Zoltan , Kisistok Judit , Sokac Mateo , Salgado Roberto , Diossy Miklos , Demeulemeester Jonas , Bunkum Abigail , Dwornik Angela , Magness Alastair , Frankell Alexander M. , Karamani Angeliki , Toncheva Antonia , Chain Benny , Castignani Carla , Bailey Chris , Abbosh Christopher , Puttick Clare , Weeden Clare E. , Lee Claudia , Richard Corentin , Hiley Crispin T. , Karagianni Despoina , Biswas Dhruva , Levi Dina , Cadieux Elizabeth Larose , Lim Emilia L. , Colliver Emma , Nye Emma , Gálvez-Cancino Felipe , Gimeno-Valiente Francisco , Kassiotis George , Stavrou Georgia , Mastrokalos Gerasimos-Theodoros , Lowe Helen L. , Matos Ignacio Garcia , Noorani Imran , Goldman Jacki , Reading James L. , Black James R. M. , Rane Jayant K. , Nicod Jerome , Hartley John A. , Peggs Karl S. , Enfield Katey S. S. , Selvaraju Kayalvizhi , Thol Kerstin , Ng Kevin W. , Chen Kezhong , Dijkstra Krijn , Grigoriadis Kristiana , Thakkar Krupa , Ensell Leah , Shah Mansi , Litovchenko Maria , Sunderland Mariana Werner , Huska Matthew R. , Dietzen Michelle , Leung Michelle M. , Escudero Mickael , Angelova Mihaela , Tanić Miljana , Kanu Nnennaya , Chervova Olga , Lucas Olivia , Al-Sawaf Othman , Prymas Paulina , Hobson Philip , Pawlik Piotr , Stone Richard Kevin , Bentham Robert , Vendramin Roberto , Saghafinia Sadegh , Gamble Samuel , Ung Seng Kuong Anakin , Vanloo Sharon , Zaccaria Simone , Hessey Sonya , Harries Sian , Boeing Stefan , Beck Stephan , Bola Supreet Kaur , Denner Tamara , Watkins Thomas B. K. , Jones Thomas Patrick , Spanswick Victoria , Barbè Vittorio , Lu Wei-Ting , Hill William , Liu Wing Kin , Wu Yin , Naito Yutaka , Ramsden Zoe , Veiga Catarina , Royle Gary , Collins-Fekete Charles-Antoine , Fraioli Francesco , Ashford Paul , Forster Martin D. , Lee Siow Ming , Borg Elaine , Falzon Mary , Papadatos-Pastos Dionysis , Wilson James , Ahmad Tanya , Procter Alexander James , Ahmed Asia , Taylor Magali N. , Nair Arjun , Lawrence David , Patrini Davide , Navani Neal , Thakrar Ricky M. , Hoogenboom Emilie Martinoni , Monk Fleur , Holding James W. , Choudhary Junaid , Bhakhri Kunal , Scarci Marco , Gorman Pat , Khiroya Reena , Stephens Robert C. M. , Wong Yien Ning Sophia , Kaplar Zoltan , Bandula Steve , Hackshaw Allan , Hacker Anne-Marie , Sharp Abigail , Smith Sean , Dhanda Harjot Kaur , Pilotti Camilla , Leslie Rachel , Grapa Anca , Zhang Hanyun , AbdulJabbar Khalid , Pan Xiaoxi , Yuan Yinyin , Chuter David , MacKenzie Mairead , Chee Serena , Alzetani Aiman , Cave Judith , Richards Jennifer , Lim Eric , De Sousa Paulo , Jordan Simon , Rice Alexandra , Raubenheimer Hilgardt , Bhayani Harshil , Ambrose Lyn , Devaraj Anand , Chavan Hema , Begum Sofina , Buderi Silviu I. , Kaniu Daniel , Malima Mpho , Booth Sarah , Nicholson Andrew G. , Fernandes Nadia , Shah Pratibha , Proli Chiara , Hewish Madeleine , Danson Sarah , Shackcloth Michael J. , Robinson Lily , Russell Peter , Blyth Kevin G. , Kidd Andrew , Dick Craig , Le Quesne John , Kirk Alan , Asif Mo , Bilancia Rocco , Kostoulas Nikos , Thomas Mathew , McGranahan Nicholas , Swanton Charles 
Published: May 2024

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.