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Treatment Represents a Key Driver of Metastatic Cancer Evolution

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Metastasis is the main cause of cancer death, yet the evolutionary processes behind it remain largely unknown. Here, through analysis of large panel-based genomic datasets from the AACR Genomics Evidence Neoplasia Information Exchange project, including 40,979 primary and metastatic tumors across 25 distinct cancer types, we explore how the evolutionary pressure of cancer metastasis shapes the selection of genomic drivers of cancer. The most commonly affected genes were TP53, MYC, and CDKN2A, with no specific pattern associated with metastatic disease. This suggests that, on a driver mutation level, the selective pressure operating in primary and metastatic tumors is similar. The most highly enriched individual driver mutations in metastatic tumors were mutations known to drive resistance to hormone therapies in breast and prostate cancer (ESR1 and AR), anti-EGFR therapy in non–small cell lung cancer (EGFR T790M), and imatinib in gastrointestinal cancer (KIT V654A). Specific mutational signatures were also associated with treatment in three cancer types, supporting clonal selection following anticancer therapy. Overall, this implies that initial acquisition of driver mutations is predominantly shaped by the tissue of origin, where specific mutations define the developing primary tumor and drive growth, immune escape, and tolerance to chromosomal instability. However, acquisition of driver mutations that contribute to metastatic disease is less specific, with the main genomic drivers of metastatic cancer evolution associating with resistance to therapy.

TidsskriftCancer Research
Sider (fra-til)2918-2927
Antal sider10
StatusUdgivet - aug. 2022

Bibliografisk note

Funding Information:
N. McGranahan reports grants from Wellcome Trust, Cancer Research UK, grants from Rosetrees Trust during the conduct of the study, and personal fees from Achilles Therapeutics outside the submitted work; in addition, N. McGra-nahan has a patent for PCT/EP2016/ 059401 issued, a patent for PCT/ EP2016/ 071471 issued, a patent for PCT/GB2018/052004 issued, and a patent for PCT/ GB2020/050221 issued. N.J. Birkbak reports grants from Lundbeck Foundation, Danish Cancer Association, Aarhus University Research Foundation, and grants from Novo Nordisk Foundation during the conduct of the study; in addition, N.J. Birkbak has a patent for quantifying homologous recombination deficiency issued, licensed, and with royalties paid from Myriad Genetics and a patent for a prognostic gene expression signature for lung cancer pending. No disclosures were reported by the other authors.

Funding Information:
The authors would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing. Interpretations are the responsibility of study authors. N.J. Birkbak is a fellow of the Lundbeck Foundation (R272-2017-4040) and acknowledges funding from Aarhus University Research Foundation (AUFF-E-2018-7-14), the Danish Cancer Society (R230-A13715), and the Novo Nordisk Foundation (NNF21OC0071483). N. McGranahan is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant number 211179/Z/18/Z), and also receives funding from Cancer Research UK Lung Cancer Centre of Excellence, Rosetrees, and the NIHR BRC at University College London Hospitals.

Publisher Copyright:
©2022 American Association for Cancer Research.

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