The evolution of lung cancer and impact of subclonal selection in TRACERxMore about Open Access at the Crick
Authors listAlexander Frankell Michelle Dietzen Maise Al Bakir Emilia Lim Takahiro Karasaki Sophie Ward Selvaraju Veeriah Emma Colliver Ariana Huebner Abigail Bunkum Mark S Hill Kristiana Grigoriadis David A Moore James RM Black Wing Kin Liu Kerstin Thol Oriol Pich Tom Watkins Cristina Naceur-Lombardelli Daniel E Cook Roberto Salgado Gareth Wilson Chris Bailey Mihaela Angelova Robert Bentham Carlos Martínez-Ruiz Christopher Abbosh Andrew G Nicholson John Le Quesne Dhruva Biswas Rachel Rosenthal Clare Puttick Sonya Hessey Claudia Lee Paulina Prymas Antonia Toncheva Jon Smith Wei Xing Jerome Nicod Gillian Price Keith M Kerr Babu Naidu Gary Middleton Kevin G Blyth Dean A Fennell Martin D Forster Siow Ming Lee Mary Falzon Madeleine Hewish Michael J Shackcloth Eric Lim Sarah Benafif Peter Russell Ekaterini Boleti Matthew G Krebs Jason F Lester Dionysis Papadatos-Pastos Tanya Ahmad Ricky M Thakrar David Lawrence Neal Navani Sam M Janes Caroline Dive Fiona H Blackhall Yvonne Summers Judith Cave Teresa Marafioti Javier Herrero Sergio A Quezada Karl S Peggs Roland F Schwarz Peter Van Loo Daniël M Miedema Nicolai Birkbak Crispin Hiley Allan Hackshaw Simone Zaccaria TRACERx Consortium Mariam Jamal-Hanjani Nicholas McGranahan Charles Swanton
Toggle all authors (81)
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.
Issue number 7957