The evolution of lung cancer and impact of subclonal selection in TRACERx
Authors: Frankell Alexander M. , Dietzen Michelle , Al Bakir Maise , Lim Emilia L. , Karasaki Takahiro , Ward Sophia , Veeriah Selvaraju , Colliver Emma , Huebner Ariana , Bunkum Abigail , Hill Mark S. , Grigoriadis Kristiana , Moore David A. , Black James R. M. , Liu Wing Kin , Thol Kerstin , Pich Oriol , Watkins Thomas B. K. , Naceur-Lombardelli Cristina , Cook Daniel E. , Salgado Roberto , Wilson Gareth A. , Bailey Chris , Angelova Mihaela , Bentham Robert , Martínez-Ruiz Carlos , Abbosh Christopher , Nicholson Andrew G. , Le Quesne John , Biswas Dhruva , Rosenthal Rachel , Puttick Clare , Hessey Sonya , Lee Claudia , Prymas Paulina , Toncheva Antonia , Smith Jon , Xing Wei , Nicod Jerome , Price Gillian , Kerr Keith M. , Naidu Babu , Middleton Gary , Blyth Kevin G. , Fennell Dean A. , Forster Martin D. , Lee Siow Ming , Falzon Mary , Hewish Madeleine , Shackcloth Michael J. , Lim Eric , Benafif Sarah , Russell Peter , Boleti Ekaterini , Krebs Matthew G. , Lester Jason F. , Papadatos-Pastos Dionysis , Ahmad Tanya , Thakrar Ricky M. , Lawrence David , Navani Neal , Janes Sam M. , Dive Caroline , Blackhall Fiona H. , Summers Yvonne , Cave Judith , Marafioti Teresa , Herrero Javier , Quezada Sergio A. , Peggs Karl S. , Schwarz Roland F. , Van Loo Peter , Miedema Daniël M. , Birkbak Nicolai J. , Hiley Crispin T. , Hackshaw Allan , Zaccaria Simone ,   TRACERx Consortium, Le Quesne John , Van Loo Peter , Bajaj Amrita , Nakas Apostolos , Sodha-Ramdeen Azmina , Ang Keng , Tufail Mohamad , Chowdhry Mohammed Fiyaz , Scotland Molly , Boyles Rebecca , Rathinam Sridhar , Wilson Claire , Marrone Domenic , Dulloo Sean , Matharu Gurdeep , Shaw Jacqui A. , Riley Joan , Primrose Lindsay , Cheyne Heather , Khalil Mohammed , Richardson Shirley , Cruickshank Tracey , Gilbert Kayleigh , Patel Akshay J. , Osman Aya , Lacson Christer , Langman Gerald , Shackleford Helen , Djearaman Madava , Kadiri Salma , Leek Angela , Hodgkinson Jack Davies , Totten Nicola , Montero Angeles , Smith Elaine , Fontaine Eustace , Granato Felice , Doran Helen , Novasio Juliette , Rammohan Kendadai , Joseph Leena , Bishop Paul , Shah Rajesh , Moss Stuart , Joshi Vijay , Crosbie Philip , Gomes Fabio , Brown Kate , Carter Mathew , Chaturvedi Anshuman , Priest Lynsey , Oliveira Pedro , Lindsay Colin R. , Clipson Alexandra , Tugwood Jonathan , Kerr Alastair , Rothwell Dominic G. , Kilgour Elaine , Aerts Hugo J. W. L. , Kaufmann Tom L. , Szallasi Zoltan , Kisistok Judit , Sokac Mateo , Diossy Miklos , Demeulemeester Jonas , Stewart Aengus , Magness Alastair , Rowan Andrew , Karamani Angeliki , Chain Benny , Campbell Brittany B. , Castignani Carla , Weeden Clare E. , Richard Corentin , Pearce David R. , Karagianni Despoina , Levi Dina , Hoxha Elena , Larose Cadieux Elizabeth , Nye Emma , Grönroos Eva , Gálvez-Cancino Felip , Athanasopoulou Foteini , Gimeno-Valiente Francisco , Kassiotis George , Stavrou Georgia , Mastrokalos Gerasimos , Zhai Haoran , Lowe Helen L. , Matos Ignacio , Goldman Jacki , Reading James L. , Rane Jayant K. , Lam Jie Min , Hartley John A. , Enfield Katey S. S. , Selvaraju Kayalvizhi , Litchfield Kevin , Ng Kevin W. , Chen Kezhong , Dijkstra Krijn , Thakkar Krupa , Ensell Leah , Shah Mansi , Vasquez Marcos , Litovchenko Maria , Werner Sunderland Mariana , Leung Michelle , Escudero Mickael , Tanić Miljana , Sivakumar Monica , Kanu Nnennaya , Chervova Olga , Lucas Olivia , Al-Sawaf Othman , Hobson Philip , Pawlik Piotr , Stone Richard Kevin , Hynds Robert E. , Vendramin Roberto , Saghafinia Sadegh , López Saioa , Gamble Samuel , Ung Seng Kuong Anakin , Vanloo Sharon , Boeing Stefan , Beck Stephan , Bola Supreet Kaur , Denner Tamara , Mourikis Thanos P. , Spanswick Victoria , Barbè Vittorio , Lu Wei-Ting , Hill William , Wu Yin , Naito Yutaka , Ramsden Zoe , Veiga Catarina , Royle Gary , Collins-Fekete Charles-Antoine , Fraioli Francesco , Ashford Paul , Clark Tristan , Borg Elaine , Wilson James , Procter Alexander James , Ahmed Asia , Taylor Magali N. , Nair Arjun , Patrini Davide , Martinoni Hoogenboom Emilie , Monk Fleur , Holding James W. , Choudhary Junaid , Bhakhri Kunal , Scarci Marco , Hayward Martin , Panagiotopoulos Nikolaos , Gorman Pat , Khiroya Reena , Stephens Robert CM. , Wong Yien Ning Sophia , Bandula Steve , Sharp Abigail , Smith Sean , Gower Nicole , Dhanda Harjot Kaur , Chan Kitty , Pilotti Camilla , Leslie Rachel , Grapa Anca , Zhang Hanyun , AbdulJabbar Khalid , Pan Xiaoxi , Yuan Yinyin , Chuter David , MacKenzie Mairead , Chee Serena , Alzetani Aiman , Scarlett Lydia , Richards Jennifer , Ingram Papawadee , Austin Silvia , 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 , Fernandes Nadia , Shah Pratibha , Proli Chiara , Danson Sarah , Robinson Lily , Dick Craig , Kirk Alan , Asif Mo , Bilancia Rocco , Kostoulas Nikos , Thomas Mathew , Jamal-Hanjani Mariam , McGranahan Nicholas , Swanton Charles 
Published: April 2023

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.