Preinvasive lung squamous cell disease: clonal architecture, transcriptomic regulation and tissue sparing therapy

Abstract

Lung cancer remains the leading cause of death from cancer worldwide, despite the addition of novel targeted and immunotherapies. Lung squamous cell cancer develops from airway basal epithelial cells through a series of preinvasive stages long before cancer is clinically detected. A diagnosis of cancer is made when these genetically disordered basal cells have invaded through the underlying basement membrane. Preinvasive lung squamous cell lesions are accessible via bronchoscopy and offer a unique insight into the molecular changes that occur in this very early stage of lung carcinogenesis. For twenty years, patients with preinvasive lesions have been referred to UCLH and recruited to a research study that enables tissue to be acquired for research purposes. Data presented in this thesis show high-grade lung squamous cell preinvasive lesions are genetically heterogenous and follow a branching evolutionary trajectory. Epithelial clonal diversity is higher amongst high grade lesions whose histology remains static. Amongst progressive lesions destined to become cancer, epithelial clonal diversity decreases over time. In some progressive lesions, cells from more than one clone invade the basement membrane. There are clonal driver mutations both shared by and unique to the lesions analysed with late driver mutations implicating a role in invasion. Single cell transcriptomic analysis shows that epithelial-mesenchymal transition occurs within high-grade preinvasive lesions. There are also differences in immune infiltrate composition between high and low-grade preinvasive lesions. High-grade preinvasive lesions are amenable to both systemic immunotherapy and endobronchial electrocautery. Electrocautery has been delivered to patients in a multicentre randomised control trial