Genomic–transcriptomic evolution in lung cancer and metastasis

Carlos Martínez-Ruiz, James R. M. Black, Clare Puttick, Mark S. Hill, Jonas Demeulemeester, Elizabeth Larose Cadieux, Kerstin Thol, Thomas P. 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 Carné Trécesson, Philip East, Nnennaya Kanu, Kevin Litchfield, Nicolai J. Birkbak, Allan Hackshaw, Stephan Beck, Peter Van Loo, Mariam Jamal-Hanjani, Charles Swanton () and Nicholas McGranahan ()
Additional contact information
Carlos Martínez-Ruiz: University College London Cancer Institute
James R. M. Black: University College London Cancer Institute
Clare Puttick: University College London Cancer Institute
Mark S. Hill: The Francis Crick Institute and University College London Cancer Institute
Jonas Demeulemeester: The Francis Crick Institute
Elizabeth Larose Cadieux: The Francis Crick Institute
Kerstin Thol: University College London Cancer Institute
Thomas P. Jones: University College London Cancer Institute
Selvaraju Veeriah: University College London Cancer Institute
Cristina Naceur-Lombardelli: University College London Cancer Institute
Antonia Toncheva: University College London Cancer Institute
Paulina Prymas: University College London Cancer Institute
Andrew Rowan: The Francis Crick Institute and University College London Cancer Institute
Sophia Ward: University College London Cancer Institute
Laura Cubitt: The Francis Crick Institute
Foteini Athanasopoulou: University College London Cancer Institute
Oriol Pich: The Francis Crick Institute and University College London Cancer Institute
Takahiro Karasaki: University College London Cancer Institute
David A. Moore: University College London Cancer Institute
Roberto Salgado: ZAS Hospitals
Emma Colliver: The Francis Crick Institute and University College London Cancer Institute
Carla Castignani: The Francis Crick Institute
Michelle Dietzen: University College London Cancer Institute
Ariana Huebner: University College London Cancer Institute
Maise Al Bakir: University College London Cancer Institute
Miljana Tanić: University College London Cancer Institute
Thomas B. K. Watkins: The Francis Crick Institute and University College London Cancer Institute
Emilia L. Lim: University College London Cancer Institute
Ali M. Al-Rashed: University College London
Danny Lang: Francis Crick Institute
James Clements: Francis Crick Institute
Daniel E. Cook: The Francis Crick Institute and University College London Cancer Institute
Rachel Rosenthal: The Francis Crick Institute and University College London Cancer Institute
Gareth A. Wilson: The Francis Crick Institute and University College London Cancer Institute
Alexander M. Frankell: University College London Cancer Institute
Sophie Carné Trécesson: The Francis Crick Institute
Philip East: The Francis Crick Institute
Nnennaya Kanu: University College London Cancer Institute
Kevin Litchfield: University College London Cancer Institute
Nicolai J. Birkbak: University College London Cancer Institute
Allan Hackshaw: Cancer Research UK & UCL Cancer Trials Centre
Stephan Beck: University College London Cancer Institute
Peter Van Loo: The Francis Crick Institute
Mariam Jamal-Hanjani: University College London Cancer Institute
Charles Swanton: University College London Cancer Institute
Nicholas McGranahan: University College London Cancer Institute

Nature, 2023, vol. 616, issue 7957, 543-552

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-05706-4

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