They reveal the origins of lung cancer in people who have never been smokers

Lung cancer is the world's leading cause of tumor-related death, and more than 2 million people are diagnosed with the disease each year. A genomic analysis of this cancer in people without a history of smoking has revealed that most of these tumors arise from the accumulation of mutations caused by natural processes in the body.

The study, which describes for the first time three molecular subtypes of this pathology in people who have never smoked, has been carried out by an international team led by researchers from the National Cancer Institute (USA), and has had the participation of the Biomedical Genomics group of the IRB Barcelona, led by Núria López-Bigas.

The conclusions derived will help to unravel the mystery about how lung cancer appears in people who have never smoked and will guide the development of more precise clinical treatments.

"What we are seeing is that there are different subtypes of lung cancer in non-smokers with different molecular characteristics and evolutionary processes and, in the future, it is possible that we will develop different treatments based on these subtypes," explains epidemiologist María Teresa Landi, researcher from the National Cancer Institute (USA) and one of the authors of the article.

Most people who develop lung cancer have a history of smoking, but 10-20% of them have never smoked. This fact occurs more frequently in women and at an earlier age than the pathology occurs in smokers.

Environmental risk factors - such as exposure to tobacco smoke, radon, air pollution, and asbestos - or previous lung disease may explain some types of lung cancer among nonsmokers, but scientists don't know yet what causes most of these tumor types.

In this large epidemiological study, the results of which have been published in Nature Genetics, researchers have used whole genome sequencing to characterize genomic changes in tumor tissue and matched normal tissue from a sample of 232 non-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.

Mutations associated with endogenous processes

The researchers analyzed tumor genomes for mutational signatures - patterns of mutations associated with specific mutational processes, such as damage from natural activities in the body (faulty DNA repair or oxidative stress) or from exposure to carcinogens - that act as the archive activities of a tumor that give clues about what caused the cancer to develop.

There is currently a catalog of known mutational signatures, although the cause of some signatures is unknown. In this study, the researchers found that most of the tumor genomes of people who never smoked had mutational signatures associated with damage to endogenous processes, that is, natural processes that take place in the body.

Because the study was limited to people who had never smoked, the researchers have not found any mutational signatures previously associated with smoking. Nor have they found such signatures among the 62 patients who had been exposed to second-hand smoke.

However, Landi cautions that they need "a larger sample size, with detailed information on exposure, to really study the impact of passive smoking on the development of lung cancer among people who have never smoked."

Three new subtypes of lung cancer in nonsmokers

Genomic analyzes have also revealed three new subtypes of lung cancer in non-smokers, to which the researchers assigned musical names based on the level of 'noise' - the number of genomic changes - from their tumors.

The predominant subtype, 'piano', is the one with the fewest mutations and appeared to be associated with the activation of progenitor cells, which are involved in the creation of new cells. It grows very slowly over many years, and it is difficult to treat because it can have many different driver mutations.

The 'mezzo-forte' subtype showed specific chromosomal changes, as well as mutations in the EGFR growth factor receptor gene, which is commonly disrupted in lung cancer, and showed faster tumor growth.

The 'strong' subtype showed a complete genome duplication - a genomic change often seen in lung cancer of smokers. This tumor subtype also grows rapidly.

"We are beginning to understand how these tumors evolve," says Landi. "This analysis shows that there is heterogeneity or diversity in lung cancer in people who have never smoked."

“The slow-growing 'piano' subtype could provide clinicians a window to detect these tumors earlier, when they are less difficult to treat. In contrast, the others have only a few important driver mutations, suggesting that they could be identified by a single biopsy and could benefit from targeted treatments, "he maintains.

Future steps will be to study people of diverse ethnic origins and geographic locations, and whose history of exposure to lung cancer risk factors is well described.

Stephen J. Chanock, director of the NCI Division of Cancer Epidemiology and Genetics, concludes: "We hope that this research on the characteristics of genomic tumors will unlock new avenues of discovery for multiple types of cancer."


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