In a new study from the National Cancer Institute, researchers did a genomic analysis of lung cancer in people with no history of smoking.
They found that a majority of these tumors arise from the accumulation of mutations caused by natural processes in the body. They found for the first time three molecular subtypes of lung cancer in people who have never smoked.
These findings can help unlock the mystery of how lung cancer arises in people who have no history of smoking and may guide the development of more precise clinical treatments.
Lung cancer is the leading cause of cancer-related deaths worldwide. Every year, more than 2 million people around the world are diagnosed with the disease.
Most people who develop lung cancer have a history of tobacco smoking, but 10% to 20% of people who develop lung cancer have never smoked.
Lung cancer in never smokers occurs more frequently in women and at an earlier age than lung cancer in smokers.
Environmental risk factors, such as exposure to secondhand tobacco smoke, radon, air pollution, and asbestos, or having had previous lung diseases, may explain some lung cancers among never smokers, but scientists still don’t know what causes the majority of these cancers.
In this study, the researchers used whole-genome sequencing to characterize the genomic changes in tumor tissue and matched normal tissue from 232 never smokers, predominantly of European descent, who had been diagnosed with non-small cell lung cancer.
The tumors included 189 adenocarcinomas (the most common type of lung cancer), 36 carcinoids, and seven other tumors of various types. The patients had not yet undergone treatment for their cancer.
The researchers discovered that a majority of the tumor genomes of never smokers bore mutational signatures linked to damage from endogenous processes, that is, natural processes that happen inside the body.
As expected, because the study was limited to never smokers, the researchers did not find any mutational signatures that have previously been associated with direct exposure to tobacco smoking.
Nor did they find those signatures among the 62 patients who had been exposed to secondhand tobacco smoke.
The genomic analyses also found three novel subtypes of lung cancer in never smokers.
The first subtype had the fewest mutations. This subtype of tumor grows extremely slowly, over many years, and is difficult to treat because it can have many different driver mutations.
The second subtype had specific chromosomal changes as well as commonly seen in lung cancer, and exhibited faster tumor growth.
The third subtype exhibited whole-genome doubling, a genomic change that is often seen in lung cancers in smokers. This subtype of tumor also grows quickly.
The team is starting to distinguish subtypes that could potentially have different approaches for prevention and treatment
A future direction of this research will be to study people of different ethnic backgrounds and geographic locations, and whose exposure history to lung cancer risk factors is well described.
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The study is published in Nature Genetics. One author of the study is epidemiologist Maria Teresa Landi, M.D., Ph.D.
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