Analysis: lung cancer in non-smokers

Even if smoking is the main risk factor for the development of lung cancer, people who have never smoked also develop this form of cancer not so rarely. In an analysis, a cancer research team was able to trace the causes of lung cancer in non-smokers back to three genetic signatures.

Researchers at the American National Cancer Institute (NCI) used genome sequencing to characterize three molecular subtypes of lung cancer in people who had never smoked. The findings could lead to the development of more effective clinical treatments for lung cancer in non-smokers. The research results were recently published in the renowned journal “Nature Genetics”.

Research into the causes of cancer in the genome

Cancer always arises from a sequence of mutations and errors in the genetic code, which trigger uncontrolled cell growth. In order to find out the exact causes of cancer, it is therefore necessary to sequence the genome in the cancer cells. Such findings also offer new possible approaches for cancer therapy.

Three subtypes of lung cancer in nonsmokers

A genomic analysis of lung cancer in people who have never smoked has now shown that most of these tumors result from the accumulation of mutations caused by natural processes in the body. It showed that there are three subtypes of lung cancer in non-smokers. The results also help to understand how lung cancer develops in non-smoking people in the first place.

“What we can see is that there are different subtypes of lung cancer in non-smokers that have different molecular characteristics and developmental processes,” confirms cancer researcher and study director Dr. Maria Teresa Landi. “In the future, we may be able to offer different treatments based on these subtypes,” predicts the epidemiologist.

Lung cancer does not only occur in smokers

As the working group explains, lung cancer is the leading cause of cancer-related deaths worldwide. Over two million people around the world are diagnosed with the disease each year. Most of those affected are smokers – but up to 20 percent have never smoked. Lung cancer in nonsmokers often occurs at an earlier age than in smokers. In addition, more women are affected by non-smoking lung cancer than men.

Environmental risk factors such as secondhand smoke, radon exposure, air pollution, asbestos exposure or previous lung diseases can explain some cases of lung cancer in non-smokers – but by no means all. Until now it was unclear how many lung cancers develop in non-smokers.

Genome analysis of lung cancer samples

To clarify this, the researchers analyzed the genome of 232 non-smokers with lung cancer. Those affected had not yet received treatment for cancer. The working group looked for mutation signatures in the genome, i.e. for patterns that are associated with certain mutation processes. This can be damage caused by faulty DNA repair or oxidative stress, as well as exposure to carcinogens.

The archive of mutations

According to the working group, the mutation signatures allow conclusions to be drawn about the development of cancer, as it is possible to trace back in an archive how the mutations accumulated. Cancer research can now fall back on a whole catalog of known mutation signatures, which is constantly being expanded.

Damage was mostly of a natural nature

Through the analysis, the researchers showed that most tumor genomes from non-smokers had mutation signatures that were caused by damage as a result of endogenous processes. This indicates that the processes in the body are natural and cannot be assigned to any external factor.

Subtype “Piano”

Lung cancers among non-smokers can be divided into three subtypes. The predominant subtype “piano” shows the fewest mutations and progresses slowly. It appears to be triggered by activation of progenitor cells and can have many different driver mutations, making it difficult to treat.

Subtype “Mezzo-Forte”

Another subtype of lung cancer is called “mezzo-forte”. According to the research team, this type of cancer is characterized by specific chromosome changes and mutations in the growth factor receptor gene “EGFR”. This gene is often changed in lung cancer. The change is associated with rapid tumor growth.

Subtype “Forte”

The “Forte” subtype was associated with a duplication of the entire genome. This genomic change is also often seen in lung cancer in smokers. Like “mezzo-forts”, tumors of this subtype grow rapidly.

Does each subtype have to be treated differently?

“We are starting to differentiate between subtypes for which there may be different approaches to prevention and treatment,” sums up Dr. Landi. The slowly growing piano subtype could, for example, be detected at an early stage using suitable diagnostic methods. In contrast, according to Dr. The Mezzo-Forte and Forte subtypes have only a few main driver mutations. This suggests that those affected could benefit from targeted treatments.

Are there more cancer subtypes than previously thought?

“We are only at the beginning of our understanding of how these tumors develop,” emphasizes the study director. The results confirm for the first time that there are differences in the lung tumors of non-smokers. The working group believes that the investigation of tumor genomic features will open up new avenues for discovery for different types of cancer and subtypes.