Somatic mutation, clonal dynamics and tumour evolution in premalignant lung disease.

Lung cancer is the leading cause of cancer-related deaths worldwide, developing in more than a million new patients annually, with 80% directly attributable to tobacco exposure. Tobacco smoke contains >60 mutagens that bind and chemically modify DNA, branding the genome with characteristic mutational patterns. Although the genomic landscape of invasive lung cancer has been increasingly well mapped, that of premalignant lung disease and normal lung epithelium has not been systematically analysed at genome-wide level. In this research programme, we will study the interplay across smoking behaviours, mutation accumulation, clonal dynamics and lung cancer evolution. First, using targeted deep sequencing of histologically normal airway epithelium, we will define the burden and patterns of somatic mutations in normal lungs and how these correlate with smoking behaviour. Secondly, we will identify the major genetic drivers of premalignant lung lesions and how they correlate with invasive cancers, using targeted gene sequencing. Thirdly, with whole genome sequencing, we will compare premalignant lesions that spontaneously regress versus those that eventually progress to invasive cancer, with a view to developing an understanding of the genomic factors associated with disease transformation. Finally, we will bring these data streams together to develop mathematical approaches for simulating clonal dynamics in early lung cancer development. These studies will enable us to model the epidemiologically defined associations between tobacco exposure and lung cancer risk; the association between initiating driver mutations and clonal expansion; and the key variables that predict future disease progression.