Genomic–transcriptomic evolution in lung cancer and metastasis
Carlos Martínez‐Ruiz, James R. Black, Clare Puttick, Mark S. Hill, Jonas Demeulemeester, Elizabeth Larose Cadieux, Kerstin Thol, Thomas Peter Jones, Selvaraju Veeriah, Cristina Naceur‐Lombardelli, Antonia Toncheva, Paulina Prymas, Andrew Rowan, Sophia Ward, Laura Cubitt, Foteini Athanasopoulou, Oriol Pich, Takahiro Karasaki, David A. Moore, Roberto Salgado, Emma Colliver, Carla Castignani, Michelle Dietzen, Ariana Huebner, Maise Al Bakir, Miljana Tanić, Thomas B.K. Watkins, Emilia L. Lim, Ali M. Al-Rashed, Danny Lang, James Clements, Daniel E. Cook, Rachel Rosenthal, Gareth A. Wilson, Alexander M. Frankell, Sophie de Carné Trécesson, Philip East, Nnennaya Kanu, Kevin Litchfield, Nicolai J. Birkbak, Allan Hackshaw, Stephan Beck, Peter Van Loo, Mariam Jamal‐Hanjani, Nicholas McGranahan, Charles Swanton, Maise Al Bakir, Emilia L. Lim, Alexander M. Frankell, Kevin Litchfield, Nicolai J. Birkbak, Peter Van Loo, J.F. Lester, Amrita Bajaj, Apostolos Nakas, Azmina Sodha-Ramdeen, Keng Ang, Mohamad Tufail, Mohammed Fiyaz Chowdhry, Molly Scotland, Rebecca Boyles, Sridhar Rathinam, Claire Wilson, Domenic Marrone, Sean Dulloo, Dean A. Fennell, Gurdeep Matharu, Jacqui Shaw, Joan Riley, Lindsay Primrose, Ekaterini Boleti, Heather Cheyne, Mohammed S. Khalil, Shirley Richardson, Tracey Cruickshank, Gillian Price, Keith M. Kerr, Sarah Benafif, Kayleigh Gilbert, Babu Naidu, Akshay J. Patel, Aya Osman, Christer Lacson, Gerald Langman, Helen Shackleford, Madava Djearaman, Salma Kadiri, Gary Middleton, Angela Leek, Jack Davies Hodgkinson, Nicola Totten, Ángeles Montero, Elaine Smith, Eustace Fontaine, Felice Granato, Helen Doran, Juliette Novasio, Kendadai Rammohan, Leena Dennis Joseph, Paul Bishop
Abstract
Abstract Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy 1 . 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 study 2,3 . 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.