Pennycuick, Adam;
(2020)
The molecular pathogenesis of squamous cell lung cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Squamous cell lung cancers are amongst the most mutated cancers known. Their cells exhibit a high burden of genomic damage, whilst healthy airway cells - even those of heavy smokers - show relatively little such damage. How and when this cancerous transformation occurs is poorly understood. Improving this understanding may lead to better treatments; prognosis for these patients at present is dire. Before the development of squamous cell lung cancer, preinvasive lesions can be found in the airways. These small, rare lesions offer a unique insight into the early stages of lung carcinogenesis. By studying their properties, we aim to understand the intermediary phase between normal cells and cancer. For over 20 years, patients with these lesions have been recruited to the UCLH Surveillance Study, undergoing serial bronchoscopy and biopsy. Here, we present a clinical and molecular analysis of this cohort. We find that high- grade and low-grade lesions behave differently, with high-grade lesions much more likely to progress to cancer. Yet a significant proportion of high-grade lesions spontaneously regress. We therefore sought to identify molecular differences between progressive and regressive high-grade lesions. Whole-genome sequencing, transcriptomic and epigenetic profiling demonstrated clear differences between the progressive and regressive groups; we present accurate models to predict outcome using any of these modalities. We identify chromosomal instability as a key pathway driving these changes, and demonstrate using external datasets that its onset may underpin the prognostic differences between histo- logically high-grade and low-grade lesions. We show that immune surveillance is strongly associated with spontaneous regression of high-grade lesions, and identify mechanisms by which progressive lesions escape immune predation. These insights offer novel therapeutic targets, by which regression may be induced.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The molecular pathogenesis of squamous cell lung cancer |
| Event: | UCL |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10117892 |
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