Lung cancer in non-smokers stems from mutations

Published 07/09/2021 06:00

The world records two million cases of the disease annually: 10% to 20% among non-smokers – (Credit: Cesar Manso/AFP – 2/1/11)

Genetic analysis of lung cancer in people without a history of smoking shows that most of these tumors arise from the accumulation of mutations caused by natural processes in the body. The study, conducted by an international team led by researchers at the US National Cancer Institute, described for the first time three molecular subtypes of lung cancer in people who have never smoked. The results were published in the journal Nature Genetics.

“What we see is that there are different subtypes of lung cancer in non-smokers who have never smoked and they have distinct molecular characteristics and evolutionary processes,” says epidemiologist Maria Theresa Landi, who led the study. “In the future, we may have different treatments based on these subtypes,” he bets.
Lung cancer is the leading cause of cancer deaths worldwide. Each year, more than 2 million people are diagnosed with the disease. Most have a history of smoking, but 10% to 20% of patients have never smoked. This type of tumor occurs more frequently in women and at an earlier age than in smokers.

Environmental risk factors such as exposure to second-hand smoke, radon, air pollution, asbestos, or previous lung disease may explain some types of lung tumors among those who have never smoked, but scientists still don’t know what causes most of these cancers.

In the epidemiological study, they used whole-genome sequencing to describe genetic changes in tumor tissue and normal tissue in 232 never-smokers, mostly of European ancestry, diagnosed with non-small cell lung cancer. The tumors included 189 adenocarcinomas (the most common), 36 adenocarcinomas, and seven other types. Patients have not yet been cured of this disease.

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Researchers have searched tumor genomes for mutational signatures, which are patterns of mutations associated with specific processes, such as damage from normal activities in the body (for example, defective DNA repair or oxidative stress) or exposure to carcinogens. These signatures act as an archive of tumor activities that lead to the accumulation of genetic variations, providing clues as to why cancer develops.


Most of the tumor genomes taken from never-smokers had mutational signals associated with damage from endogenous processes, that is, the natural processes that occur within the body. Genomic analyzes also revealed three new lung cancer subtypes in non-smokers, with completely different developmental profiles.

“We’re beginning to distinguish between subtypes that may have different approaches to prevention and treatment,” Landy says. For example, slow-growing cancers can give doctors a chance to detect these tumors early, when they are less difficult to treat. By contrast, the other two have a few major mutations, suggesting they can be identified with a single biopsy and benefit from targeted therapies, the scientist says.

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