Multi-region whole-genome sequencing reveals gene-by-environment heterogeneity in metastatic lung cancer. Multi-region WGS of treatment naive lung cancers

Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early- stage surgical specimens. Here we used endoscopic sampling of paired primary and metastatic tumors to study inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Tumors in ever smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread.