Long considered a disease that almost exclusively affects smokers, lung cancer is increasingly changing its face. Globally, health experts are watching a disturbing trend with growing concern: a rise in the number of lung cancer cases among people who have never smoked. This form of the disease disproportionately affects women, especially those of Asian descent, and has a higher prevalence in East Asian nations compared to the Western world. While the public health focus has been on combating tobacco for decades, it has become clear that other environmental factors play a key, yet insufficiently understood, role. Recent scientific discoveries are finally shedding new light on this complex issue, offering the first concrete genomic evidence linking air pollution to the development of this malignant disease in non-smokers.

Genomic investigation reveals a hidden culprit

A revolutionary study, published last week in the prestigious scientific journal Nature, provides the most compelling evidence to date identifying air pollution and other environmental exposures as major drivers of lung cancer in non-smokers. The research, jointly conducted by scientists at the University of California, San Diego (UC San Diego) and the National Cancer Institute (NCI), part of the U.S. National Institutes of Health (NIH), represents a turning point in understanding this disease. Previous studies have mostly pointed to an epidemiological link, but this research goes a step further, delving deep into the tumor genome to uncover the molecular mechanisms by which environmental factors damage DNA and promote cancer development.

Dr. Ludmil Alexandrov, a professor of bioengineering and cellular and molecular medicine at UC San Diego and one of the study leaders, emphasizes the importance of this discovery. "We are facing a problematic trend of rising lung cancer in non-smokers, and until now, we haven't fully understood why. Our research shows that air pollution is strongly associated with the same types of DNA mutations that we typically associate with smoking," Alexandrov pointed out. His colleague, Dr. Maria Teresa Landi, an epidemiologist at the NCI, adds: "This is an urgent and growing global problem. Most previous studies did not separate data from smokers and non-smokers, which limited insight into the potential causes in these patients. We designed the study to collect data from non-smokers worldwide and use genomics to find clues of exposures that could be causing these cancers."

Molecular fingerprints in our cells

The scientific team analyzed lung tumors from 871 non-smokers living in 28 different regions across Africa, Asia, Europe, and North America, covering areas with varying levels of air pollution. Using an advanced whole-genome sequencing technique, the researchers identified specific patterns of DNA mutations, known as mutational signatures. These signatures act like molecular fingerprints, leaving a permanent record of past exposures that have damaged the cell's genetic material. By combining genomic data with pollution estimates based on satellite and ground-based measurements of fine particulate matter (PM2.5), they were able to estimate individuals' long-term exposure to polluted air.

The results were unequivocal. Non-smokers living in more polluted environments had a significantly higher number of mutations in their lung tumors. Particularly prominent were so-called "driver" mutations, which directly promote cancer development, and mutational signatures associated with cancer. For instance, these individuals showed a 3.9-fold increase in the mutational signature typically associated with tobacco smoking and a 76% greater increase in another signature linked to aging. Marcos Díaz-Gay, one of the study's authors, clarifies that this does not mean pollution creates a unique "air pollution signature," but rather that it increases the total number of mutations, especially within known DNA damage pathways. "What we see is that air pollution is associated with an increase in somatic mutations, including those that fall under known mutational signatures attributed to smoking and aging," says Díaz-Gay.

The researchers also observed a clear dose-response relationship: the more an individual was exposed to pollution, the more mutations were found in their lung tumors. Additionally, these tumors had shorter telomeres, the protective caps at the ends of chromosomes, which is a clear sign of accelerated cellular aging.

Surprising results: The role of passive smoking and herbal medicines

In contrast to the strong link with air pollution, the researchers did not find a strong genetic correlation with passive smoking. Lung tumors of non-smokers exposed to passive smoking showed only a slight increase in mutations, along with shorter telomeres, but without specific mutational signatures or "driver" mutations. Although exposure to passive smoking is a known risk factor for cancer, its mutagenic effect was far less pronounced than that seen with air pollution. The scientists suggest that the mutagenic effect of passive smoking may be too weak to be detected with current tools, although its biological effects are visible in the significant shortening of telomeres.

Besides air pollution, the study identified another environmental risk: aristolochic acid, a potent carcinogen found in certain traditional Chinese herbal medicines. A specific mutational signature associated with this acid was found almost exclusively in cases of lung cancer in non-smokers from Taiwan. Although aristolochic acid has previously been linked to bladder, digestive tract, kidney, and liver cancer due to ingestion, this is the first study to provide evidence that it could also contribute to lung cancer. Researchers suspect this could occur through the inhalation of vapors from traditional herbal preparations, but further research will be needed to confirm this hypothesis. "This raises a new concern about how traditional medicines may unintentionally increase cancer risk, but at the same time, it presents an opportunity for prevention, especially in Asia," commented Dr. Landi.

The mystery of the new signature and the future of research

In another intriguing discovery, the team identified a completely new mutational signature that appears in the lung tumors of most non-smokers but is absent in smokers. Its cause remains unknown—it did not correlate with air pollution or any other known environmental exposure. "We see it in most cases in this study, but we don't yet know what triggers it," said Alexandrov. "This is something completely different and opens up a whole new area of research."

Looking ahead, the researchers plan to expand their study to include lung cancer cases in non-smokers from Latin America, the Middle East, and additional regions of Africa. They are also turning their attention to other potential risks. One focus is the use of marijuana and e-cigarettes, especially among younger people who have never smoked tobacco, to investigate whether these exposures also contribute to mutational changes in lung tissue. Their goal is to study other environmental risks, such as radon and asbestos, and to collect more detailed pollution data at the local and individual levels to create an even more complete picture of the causes of this increasingly common disease.

Source: University of California