This study analyzed 1,644 tumor regions from 421 non-small cell lung cancer (NSCLC) patients in the TRACERx study. In lung adenocarcinoma, subclonal selection was observed in many cancer genes, including TP53 and KRAS. Evolutionary dependencies between drivers, mutational processes, and whole genome doubling (WGD) events were identified. 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. Large subclonal expansions were associated with shorter disease-free survival. Subclonal WGD was associated with shorter disease-free survival, and copy number heterogeneity with extrathoracic relapse. The study highlights the importance of clonal expansion, WGD, and copy number instability in NSCLC relapse.

A M Frankell, M Degasperi, M A Bakir, E L Lee, T Kowiata, S Wedge, J Niblett, S Vowler, C N-L, E Colliver, A Huebner, A Bailey, D A Martin, M S Jamal-Hanjani, D C Chan, G A Wedge, C Martinez-Ruiz, C Burrell, D Bunn, R Ramakrishna, M Andronis, C P Barnes, R Bhakta, R Salm, P Van Loo, J Haigh, J Snelgrove, W Xuan, K Grigoriadis, J R M Bell, O Peeters, T B K Watkins, C Thway, S Quezada, K S Phillips, P Van Loo, R F Simcox, C D S Zehir, M Jones, M J-H, N McGranahan, C Swanton