Lung cancer is often associated with tobacco use. Yet, a significant proportion of patients have never smoked. A large international study published in the prestigious journal Nature, to which Professor Paul Hofman, a member of IHU RespirERA, contributed, shows that lung cancers do not all evolve in the same way depending on patient profiles. These findings open up new perspectives to better understand the disease and, ultimately, to improve prevention and treatment strategies.
A Better Understanding of Lung Cancer Evolution
Researchers analyzed more than 1,000 lung adenocarcinomas—the most common form of lung cancer—by combining highly detailed genetic data with other biological information, using what is known as a “multi-omics” approach.
The goal was to reconstruct the history of the cancer, from the earliest cellular alterations to tumor development, in order to identify the mechanisms that drive its progression.
Different Cancers Depending on Tobacco Exposure
The study highlights clear differences between lung cancers in smokers and in never smokers.
In smokers, tumors carry numerous mutations directly linked to tobacco exposure, particularly affecting the KRAS gene. Their progression is often rapid, with limited diversification of cancer cells.
In people who have never smoked, lung cancers follow a different trajectory. Researchers observed early alterations in the number of copies of certain genes, as well as mutations in the EGFR gene, which are well known in thoracic oncology.
These differences show that tobacco not only influences the risk of developing lung cancer, but also the way the disease evolves over time.
Sex and Geographic Origin Also Play a Role
The study also reveals that sex and geographic origin influence the evolution of lung cancer in never smokers.
For example, some tumors in women of European origin progress very slowly, sometimes over several years, before being detected. In contrast, among Asian patients who have never smoked, tumor progression can be faster. These findings highlight the importance of personalized approaches to screening and patient follow-up.
A Key Discovery: An Aggressive and Previously Underrecognized Mechanism
Researchers identified a specific genetic signature, known as ID2, associated with a mechanism that has so far been poorly recognized in lung cancer. This signature is linked to the reactivation of ancient genetic elements present in our DNA, called LINE-1 elements.
When reactivated, these elements cause major genomic instability, making tumors more aggressive, more likely to metastasize, and associated with poorer outcomes. Identifying this mechanism could, in the future, help detect the most aggressive forms of lung cancer at an earlier stage.
Toward More Targeted Screening and Treatments
This study illustrates the complexity of lung cancer, but also the opportunities created by a better understanding of its evolution. By identifying distinct trajectories based on smoking status, sex, and origin, research is paving the way for more tailored screening strategies and increasingly personalized treatments.
The work to which Professor Paul Hofman contributed fully aligns with the mission of IHU RespirERA: to improve understanding of respiratory diseases, reduce their impact on the population, and enhance respiratory health for all.
Link to the publication: Uncovering the role of LINE-1 in the evolution of lung adenocarcinoma.
