Genomic–transcriptomic evolution in lung cancer and metastasis
Authors: Martínez-Ruiz Carlos , Black James R. M. , Puttick Clare , Hill Mark S. , Demeulemeester Jonas , Larose Cadieux Elizabeth , Thol Kerstin , Jones Thomas P. , Veeriah Selvaraju , Naceur-Lombardelli Cristina , Toncheva Antonia , Prymas Paulina , Rowan Andrew , Ward Sophia , Cubitt Laura , Athanasopoulou Foteini , Pich Oriol , Karasaki Takahiro , Moore David A. , Salgado Roberto , Colliver Emma , Castignani Carla , Dietzen Michelle , Huebner Ariana , Al Bakir Maise , Tanić Miljana , Watkins Thomas B. K. , Lim Emilia L. , Al-Rashed Ali M. , Lang Danny , Clements James , Cook Daniel E. , Rosenthal Rachel , Wilson Gareth A. , Frankell Alexander M. , de Carné Trécesson Sophie , East Philip , Kanu Nnennaya , Litchfield Kevin , Birkbak Nicolai J. , Hackshaw Allan , Beck Stephan , Van Loo Peter , Jamal-Hanjani Mariam ,   TRACERx Consortium, McGranahan Nicholas , Swanton Charles , Bakir Maise Al , Lim Emilia L. , Frankell Alexander M. , Litchfield Kevin , Birkbak Nicolai J. , Van Loo Peter , Lester Jason F. , 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 , Fennell Dean A. , Matharu Gurdeep , Shaw Jacqui A. , Riley Joan , Primrose Lindsay , Boleti Ekaterini , Cheyne Heather , Khalil Mohammed , Richardson Shirley , Cruickshank Tracey , Price Gillian , Kerr Keith M. , Benafif Sarah , Gilbert Kayleigh , Naidu Babu , Patel Akshay J. , Osman Aya , Lacson Christer , Langman Gerald , Shackleford Helen , Djearaman Madava , Kadiri Salma , Middleton Gary , 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. , Blackhall Fiona H. , Krebs Matthew G. , Summers Yvonne , Clipson Alexandra , Tugwood Jonathan , Kerr Alastair , Rothwell Dominic G. , Kilgour Elaine , Dive Caroline , Aerts Hugo J. W. L. , Schwarz Roland F. , Kaufmann Tom L. , Szallasi Zoltan , Kisistok Judit , Sokac Mateo , Diossy Miklos , Bunkum Abigail , Stewart Aengus , Magness Alastair , Karamani Angeliki , Chain Benny , Campbell Brittany B. , Bailey Chris , Abbosh Christopher , Weeden Clare E. , Lee Claudia , Richard Corentin , Hiley Crispin T. , Pearce David R. , Karagianni Despoina , Biswas Dhruva , Levi Dina , Hoxha Elena , Nye Emma , Grönroos Eva , Gálvez-Cancino Felip , Gimeno-Valiente Francisco , Kassiotis George , Stavrou Georgia , Mastrokalos Gerasimos , Zhai Haoran , Lowe Helen L. , Matos Ignacio Garcia , Goldman Jacki , Reading James L. , Herrero Javier , Rane Jayant K. , Nicod Jerome , Lam Jie Min , Hartley John A. , Peggs Karl S. , Enfield Katey S. S. , Selvaraju Kayalvizhi , Ng Kevin W. , Chen Kezhong , Dijkstra Krijn , Grigoriadis Kristiana , Thakkar Krupa , Ensell Leah , Shah Mansi , Duran Marcos Vasquez , Litovchenko Maria , Sunderland Mariana Werner , Leung Michelle , Escudero Mickael , Angelova Mihaela , Sivakumar Monica , Chervova Olga , Lucas Olivia , Al-Sawaf Othman , Hobson Philip , Pawlik Piotr , Stone Richard Kevin , Bentham Robert , Hynds Robert E. , Vendramin Roberto , Saghafinia Sadegh , López Saioa , Gamble Samuel , Ung Seng Kuong Anakin , Quezada Sergio A. , Vanloo Sharon , Zaccaria Simone , Hessey Sonya , Boeing Stefan , Bola Supreet Kaur , Denner Tamara , Marafioti Teresa , Mourikis Thanos P. , 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 , Clark Tristan , 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. , Janes Sam M. , Hoogenboom Emilie Martinoni , Monk Fleur , Holding James W. , Choudhary Junaid , Bhakhri Kunal , Scarci Marco , Hayward Martin , Panagiotopoulos Nikolaos , Gorman Pat , Khiroya Reena , Stephens Robert C. M. , 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 , Cave Judith , Scarlett Lydia , Richards Jennifer , Ingram Papawadee , Austin Silvia , 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. , Dick Craig , Le Quesne John , Kirk Alan , Asif Mo , Bilancia Rocco , Kostoulas Nikos , Thomas Mathew , Swanton Charles , McGranahan Nicholas 
Published: April 2023

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.