Lung Cancer: How Lung Cancer Occurs in Non-smokers Revealed

The National Institutes of Health (NIH), part of the US Department of Health and Human Services, has revealed the mystery of how lung cancer occurs in people who have never smoked and can guide the development of more precise clinical treatments. Genomic analysis of lung cancer in people with no history of smoking has revealed that the majority of these tumors result from the accumulation of mutations caused by natural processes in the body.

This study was conducted by an international team led by researchers at the National Cancer Institute (NCI), which is part of the National Institutes of Health (NIH) and for the first time described three molecular subtypes of lung cancer in people never smoked. The results were published earlier this week in Nature Genetics.

“What we are finding is that there are different subtypes of lung cancer in non-smokers that have distinct molecular characteristics and evolutionary processes,” said epidemiologist Maria Teresa Landi, MD, Ph .D., Of the integrative tumor epidemiology branch of the NCI division. of Cancer Epidemiology and Genetics, who led the study, which was done in collaboration with researchers from the National Institute of Environmental Health Sciences, another part of the NIH and other institutions. “In the future, we may be able to have different treatments based on these subtypes.”

Lung cancer is the leading cause of cancer-related deaths worldwide. Each year, more than 2 million people around the world are diagnosed with the disease. Environmental risk factors, such as exposure to radon, air pollution and asbestos, or having had previous lung diseases, may explain some lung cancers in non-smokers. , but scientists still don’t know what causes the majority of these cancers.

In this large epidemiological study, researchers used whole genome sequencing to characterize genomic changes in tumor tissue and compared normal tissues of 232 never smokers, mostly of European origin, who had been diagnosed with cancer. non-small cell lung. 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 received treatment for their cancer.

Researchers combed tumor genomes for mutational signatures, which are patterns of mutations associated with specific mutational processes, such as damage caused by natural activities in the body (for example, faulty repair of DNA or oxidative stress) or exposure to carcinogens. Mutational signatures act as a archive of tumor activities that led to the accumulation of mutations, providing clues as to what caused the cancer to develop. A catalog of known mutational signatures now exists, although some signatures have no known cause. In this study, the researchers found that the majority of the tumor genomes of non-smokers carried mutational signatures associated with damage caused by endogenous processes, that is, natural processes that occur inside the body. body.

As expected, since the study was limited to people who have never smoked, the researchers found no mutational signatures previously associated with direct exposure to smoking.

Genomic analyzes also revealed three new subtypes of lung cancer in non-smokers, to which the researchers assigned musical names based on the level of “noise” (that is, the number of genomic changes ) in tumors. The predominant subtype “piano” had the fewest mutations; it appears to be associated with the activation of progenitor cells, which are involved in the creation of new cells.

This tumor subtype grows extremely slowly, over many years, and is difficult to treat because it can have many different motor mutations. The “mezzo-forte” subtype exhibited specific chromosomal changes as well as mutations in the growth factor receptor gene EGFR, which is commonly altered in lung cancer, and exhibited faster tumor growth. The strong subtype exhibited whole genome doubling, a genomic change often seen in lung cancer in smokers. This tumor subtype also grows rapidly.

“We are starting to distinguish subtypes that could potentially have different approaches to prevention and treatment,” said Dr Landi. For example, the slow-growing piano subtype might give clinicians a window of opportunity to detect these tumors earlier when they are less difficult to treat. In contrast, the mezzo-forte and forte subtypes show only a few major motor mutations, suggesting that these tumors could be identified with a single biopsy and could benefit from targeted treatments, she said.

A future direction of this research will be to study people of different ethnic origins and geographic locations, and whose history of exposure to lung cancer risk factors is well described.

“We are starting to understand how these tumors evolve,” said Dr Landi. This analysis shows that there is heterogeneity, or diversity, in lung cancer in non-smokers. ”

Stephen J. Chanock, MD, director of NCI’s Division of Cancer Epidemiology and Genetics, said: “We expect this detective-style investigation into the characteristics of genomic tumors to open up new avenues of investigation. discovery for several types of cancer.

The study was conducted by NCI’s intramural research program and the National Institute of Environmental Health Sciences.

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