Smoking is the number one cause of lung cancer, and most research into lung tumors is based on samples taken from smokers. But even people who have never smoked can get lung cancer. A study now shows that they have different mutation patterns than those of smokers. According to this, three subtypes are common among non-smokers, which develop differently and have different genetic signatures. The results could contribute to more individual cancer treatment in the future.
Lung cancer is the leading cause of cancer-related deaths worldwide. There are more than two million new patients each year. Most of them smoked tobacco. Ten to 25 percent of those affected, however, have never smoked. It is known that lung cancer in non-smokers is more common in women and typically at a younger age than lung cancer in smokers. The reasons for this have not yet been fully clarified. Environmental risk factors such as secondhand smoke, radon, air pollution, and asbestos or previous lung diseases can explain some cases of lung cancer in nonsmokers, but in the majority of cases the cause was unclear.
Tracking down the causes of tumors
A team led by Tongwu Zhang from the US National Cancer Institute in Bethesda has now investigated the causes of lung cancer in non-smokers. To do this, the researchers examined samples from 232 lung cancer patients who had never smoked in their lives. The samples were taken before the patients began treatment. Zhang and his colleagues analyzed so-called mutation signatures, i.e. specific mutation patterns in the genome of cancer cells, the origins of which can be traced back to certain triggers. For example, if the mutations are due to natural processes in the body, such as faulty DNA repair or oxidative stress, they have a different genetic signature than if they were triggered by carcinogens. In this way, mutation signatures provide clues as to the cause of the cancer development.
“We have found that there are different subtypes of lung cancer in non-smokers that have different molecular characteristics and development processes and that differ significantly from typical lung tumors in smokers,” reports Zhang’s colleague Maria Teresa Landi. While the influence of the carcinogen tobacco can usually be seen in smokers’ tumors, the analysis shows that the mutation signatures in non-smokers mainly indicate damage caused by the body’s own processes. In almost half of the tumors, the researchers found a signature that indicates damage from oxidative stress.
Different mutations
On average, the mutation load in the tumors of nonsmokers was seven times lower than that of smokers. Based on the number of genomic changes, the researchers divided the lung tumors in non-smokers into three subtypes, which they named based on musical volume information. Almost half of all non-smoking lung tumors therefore belong to the piano subtype. This has only a few mutations and grows very slowly. In many cases, the UBA1 gene, which is involved in the repair of DNA damage, has been changed here. However, because the piano subtype can have a variety of different driver mutations, it is difficult to treat.
The Mezzo-Forte subtype is characterized by specific chromosome changes and in more than half of all cases has mutations in the growth factor receptor gene EGFR, which leads to faster tumor growth. In comparable smoking tumors, this mutation occurs in just under one in ten. The likewise fast-growing Forte subtype, which occurred in around one in five non-smokers, shows a doubling of the entire genome – a change that occurs significantly more frequently in smokers’ tumors, in more than every second case.
More targeted treatments for non-smokers
However, the researchers did not find mutation signatures associated with direct exposure to tobacco smoke in any of the non-smokers examined. This also applied to 62 test persons who stated that they had been exposed to secondhand smoke in their lives. However, due to the small sample size and the very different exposure of the test persons, it cannot be said with certainty whether passive smoking actually only played a subordinate role in the disease. “We need a larger sample with detailed exposure information to really study the effects of secondhand smoke on the development of lung cancer in nonsmokers,” says Landi.
The results of the study could help treat lung cancer in non-smokers in a more targeted manner in the future. “There may be different approaches to prevention and treatment for the different subtypes that we distinguish,” says Landi. The slowly growing piano subtype could give doctors a chance to discover and treat precursor cells of these tumors at an early stage. The Mezzo-Forte and Forte subtypes, on the other hand, have only a few main driver mutations, so that patients could particularly benefit from chemotherapies tailored to them. In future studies, the researchers want to review and deepen their results on larger patient groups.
Source: Tongwu Zhang (National Cancer Institute, Bethesda, USA) et al., Nature Genetics, doi: 10.1038 / s41588-021-00920-0