How lung cancer develops in people who have never smoked

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Each year, more than two million people are diagnosed with lung cancer, one of the deadliest types of cancer. Although most people with lung cancer have smoked tobacco, about a quarter of people who develop lung cancer have never smoked.

Second-hand smoke, radon, air pollution and asbestos are risk factors for lung cancer. However, when Maria Teresa Landi, an epidemiologist in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and her colleagues sequenced more than 200 lung cancers in non-smokers, they found no genetic signatures linked to exposure to second-hand tobacco smoke.

Instead, these tumors, which fall into three subtypes, result from the build-up of mutations from natural processes in the body. The different subtypes could lead to new approaches to prevention and treatment.

“It’s a historic document for us to understand what motivates lung cancer in non-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 declined, the proportion of lung cancer patients who have never smoked has increased. “It’s a very serious illness and unfortunately quite common now,” Landi said. For the new study published in Genetics of natureShe and a host of collaborators have begun to unravel what causes lung cancer in non-smokers and how the disease progresses.

Smoking cigarettes is a major risk factor for developing lung cancer, but the disease is on the increase in people who have never smoked.

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Landi and his colleagues sequenced the entire genomes of tumor samples and the germline DNA of the participants. By evaluating the genomic material at the time of lung cancer diagnosis, the researchers deduced what had happened many years ago that led to the development of tumors.

The team’s analysis revealed that endogenous processes generated most of the signatures in tumors of non-smokers. Compared to the tumors of smokers, the total number of mutations in the tumors of non-smokers was more than seven times lower.

Landi and his colleagues have also identified three major subtypes of cancer based on genomic changes known as copy number alterations, mutations that occur when pieces of chromosomes are duplicated, amplified, or deleted. These tumor subtypes differed in the way they grew. Some tumors appear at an older age, but grow quite quickly. In another subtype, the mutations that would eventually lead to cancer occurred at much younger ages, but grew much slower, taking up to ten years to manifest.

The differences between the subtypes provided advantages and disadvantages with regard to treatment approaches. Landi and his team found that only a few genomic changes stimulated the growth of rapidly growing lung cancers, meaning that rapidly growing tumors could potentially be targeted with specific treatments against the few mutations.

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

“They did such comprehensive analyzes,” Amos said. “It’s pretty amazing how much information is in this article. “

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

They also conduct an extensive analysis of electronic health records to determine whether certain medical conditions or long-term drug use play a role in the development of lung cancer in non-smokers.

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

Reference

T. Zhang et al., “Genomic and evolutionary classification of lung cancer in non-smokers”, Nat Genet, 53 (9): 1348-59, 2021.


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