How lung cancer develops in people who have never smoked

Every year more than two million people develop lung cancer, one of the deadliest types of cancer. Although most people with lung cancer have smoked tobacco in the past, around a quarter of people with lung cancer have never smoked.

Secondhand smoke, radon, air pollution and asbestos are risk factors for lung cancer. However, when Maria Teresa Landi, an epidemiologist with the National Cancer Institute’s Department of Cancer Epidemiology and Genetics, and her colleagues sequenced more than 200 lung cancers in nonsmokers, they found no genetic signatures associated with secondhand smoke exposure.

Instead, these tumors, which are divided into three subtypes, arose from the accumulation of mutations from natural processes in the body. The different subtypes could open up new approaches for prevention and treatment.

“It’s a landmark paper for us to understand what drives lung cancer in never-smokers,” said Chris Amos, an epidemiologist at Baylor College of Medicine, who was not involved in the new work.

Although the incidence of lung cancer has decreased, the proportion of lung cancer patients who have never smoked has increased. “It is now a very serious and unfortunately quite common disease,” said Landi. For the new study published in Natural genetics, she and a variety of staff began to find out what causes lung cancer in nonsmokers and how the disease develops.

Cigarette smoking is a major risk factor for developing lung cancer, but the disease is increasing in people who have never smoked.


Landi and colleagues sequenced the entire genomes of tumor samples and germline DNA from participants. From the analysis of the genome material at the time of lung cancer diagnosis, the researchers deduced what led to the development of the tumors many years earlier.

The team’s analysis revealed that most of the signatures in nonsmokers’ tumors were generated by endogenous processes. Compared to tumors from smokers, the total number of mutations in tumors from never-smokers was more than seven times lower.

Landi and her colleagues also identified three major cancer subtypes based on genomic changes known as copy number changes, mutations that occur when pieces of chromosome are duplicated, amplified, or deleted. These tumor subtypes differed in their development. Some tumors appeared in old age, but grew quite quickly. In another subtype, mutations that eventually led to cancer appeared at a much younger age, but grew much more slowly and took up to ten years to manifest.

The differences between the subtypes offered advantages and disadvantages in terms of treatment approaches. Landi and her team found that few genomic changes fueled the growth of fast-growing lung cancers, meaning that the fast-growing tumors could potentially be targeted against the few mutations with specific treatments.

In contrast, slow-growing tumors had heterogeneous mutations that made them more difficult to treat with targeted therapies. However, patients with slowly growing tumors developed symptoms and there was a window of time for early detection and diagnosis.

“They did such extensive analysis,” said Amos. “It’s amazing how much information is in this newspaper.”

For Landi, this study is just the beginning. She hopes to identify markers that can be used to screen people who may be at higher risk of developing these types of tumors. She and her team are pursuing this goal in a number of ways, including expanding the study to a much larger population that includes subjects from broader ethnic and geographic backgrounds.

They also perform an extensive analysis of electronic health records to investigate whether certain medical conditions or long-term use of drugs play a role in the development of lung cancer in the non-smoking population.

This combination of approaches “could potentially lead to the development of much-needed screening strategies,” Landi said.


T. Zhang et al., “Genomic and Evolutionary Classification of Lung Cancer in Never Smokers”, Nat Genet, 53 (9): 1348-59, 2021.

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