Abstract
Abstract
While chronic obstructive pulmonary disease (COPD) and lung cancer can be attributed in the main to cigarette smoking, and together account for over 50% of all smoking-related deaths, their degree of relatedness is not well understood. Although smoking accounts for about 80-90% of all cases, studies suggest that genetic susceptibility may explain in part why some smokers are more susceptible than others, to these complications from smoking. Recent evidence suggests that an exaggerated innate immune response to smoking, reflected in elevation of systemic inflammation mediators, may underlie this overlapping susceptibility. In recent years, there has been a growing interest in the potential for immune modulation in preventing or delaying the development of COPD and/or lung cancer. Lastly, there is now strong evidence that screening for lung cancer is effective in reducing lung cancer related deaths although debate exists as to whom it is best to screen.
This thesis presents 92 peer-reviewed publications that includes; 23 original studies, 8 invited editorials, 18 review articles, 40 letters and 3 key abstracts. These publications are representative of how my epidemiological observations and research has provided new insights into the strong relationship found between COPD and lung cancer as well as explaining and confirming previous observations.
This body of work describes my hypotheses, observations and research results which build on prior knowledge and gives a new understanding of the significance of the COPD/lung cancer connection in the context of smoking exposure. My hypotheses are presented in six chapters as outlined below.
1. COPD and lung cancer result from an exaggerated innate immune response and have overlapping pathophysiological pathways mediated in part by genetic factors. I propose that it is important to examine the origins and outcomes from lung cancer with a greater understanding of the role of COPD. Through this body of work I hypothesise that COPD and lung cancer result from aberrant immune responses that are open to modification from systemic approaches (see below) and that they are directly related through overlapping genetic pathways via smoking-by-gene, gene-by-gene and smoking-by-ethnicity effects (Chapter 1).
2. The genetic basis of lung cancer is in part mediated by genetic susceptibility to COPD. Identifying this relationship requires extensive use of spirometry in genetic studies of lung cancer. I propose that by ignoring this overlapping genetic effect, the potential for confounding exists due to a failure to realise the important effect that COPD has on lung cancer biology and hence outcomes. Lastly this work identifies that the nicotinic receptor gene (CHRNA, Chr 15q25) is one of the most significant overlapping genetic factors underlying COPD and lung cancer risk, this finding has great relevance to the recent increase in nicotine-based vaping (Chapter 2).
3. It is possible to combine genetic risk variants with clinical variables to develop a personalised gene-based approach to assessing risk of lung cancer, and that this requires validation in different cohorts in prospective studies. My work also proposes that there is evidence from psychological models, and pilot clinical studies, to suggest that smokers may respond positively to knowing their genetic risk in the context of quitting smoking and participating in lung cancer screening (Chapter 3).
4. The risk of developing COPD and lung cancer may be reduced through modification of the innate immune system where drugs such as statins (HMG-CoA reductase inhibitors), (Chapter 4), and high fibre diets (Chapter 5), can directly attenuate systemic inflammation (primarily driven by IL-6) and confer protective effects in smokers. This effect may reduce hospitalisation and death from COPD and/or lung cancer.
5. By better understanding the important effects of COPD on lung cancer diagnosed early through screening, outcomes from screening can be optimised. I also show that for lung cancer screening, high rates of unrecognised COPD drastically affects outcomes through reduced life expectancy and lower surgical rates, making lung cancer screening very different to that of bowel and breast cancer screening (Chapter 6).
I conclude that COPD and lung cancer are closely related on a genetic, epidemiologic and pathophysiological basis. I contend that the routine use of spirometry to better characterise high risk smokers has a useful role in optimising outcomes and reducing mortality.