2021 LCRF Research Grant on Disparities in Lung Cancer
Mariam Jamal-Hanjani, MD, PhD
University College London Cancer Institute
Research Project:
Investigating the association between air pollution and EGFR mutant never smoker lung cancer
Summary:
Lung cancer in people who have never smoked has a marked gender bias, occurs more frequently in women, and has a disproportionately high incidence in people of Asian ethnicity. We are yet to determine the causes of lung cancer in this population, and whilst it is known that air pollution is a major risk factor for lung cancer, especially for people who have never smoked, the process by which this occurs remains unknown. This project aims to examine the genetics of normal lung tissues to identify any abnormalities that may predispose never-smoker patients to developing lung cancer, and in particular, to investigate whether this is facilitated by exposure to air pollution.
Ultimately, the aim is to understand the alternative causes of lung cancer which may impact the way in which we screen for the disease in high risk, under-served populations, and may also inform early interventional strategies to prevent cancer development.
Final report:
This project explored the presence of EGFR mutant clones in normal human tissue from patients with lung cancer and patients who never developed lung cancer. Using DNA profiling oncogenic driver mutations were identified in 19% of normal lung tissue samples from patients with lung cancer and 16% of patients who never developed lung cancer. 18% of normal samples had EGFR mutations and 53% had KRAS mutations. There was a positive relationship between anthracosis and EGFR mutations. There was no association between EGFR and KRAS mutations in non-cancerous tissue and smoking status or cancer diagnosis. The strongest association with EGFR mutations in normal tissue was with female sex.
Impact:
This project has potential for tremendous impact. The discovery of oncogenic driver mutations in normal lung tissue could potentially help us understand why never-smoking patients develop lung cancer. This is particularly important in women who have a higher tendency to develop never-smoking lung cancer. There are some suggestions that exposure to environmental pollutants could promote this. The grantee has obtained funding to extend her research to include other driver mutations and to study the Asian population that has some of the highest rates of never-smoking lung cancer. This research could provide invaluable support for the early detection of lung cancer in patients who would not normally be considered at risk. There is also the potential to develop prevention strategies.
Future plans:
Research has begun to begin examining normal tissue for the presence of mutations in other lung cancer driver genes, such as KRAS, BRAF, TP53. The hope is that this will provide a more comprehensive understanding of which mutant clones are selected for by pollution exposure. A new study that has emerged because of this work is an effort to examine normal lung tissue from a cohort of Asian individuals from Singapore, Taiwan, and Japan. This could ascertain if there are specific ethnicity-dependent characteristics of normal tissue that would promote the selection of specific mutant clones. Follow-on funding has been obtained from the Mark Foundation and an application has been submitted to the Cancer Research UK Prevention and Population Research Committee Award. There have been several presentations and publication in the high impact journal Nature.