Editor’s Pick: Why Do People Who Never Smoke Get Lung Cancer?

In modern society, with increasing life expectancy, changing lifestyles and increasing pollutants, the incidence of cancer is also increasing. Among many cancers, lung cancer is undoubtedly one of the most terrifying cancers, and its morbidity and mortality are at the forefront of malignant tumors.

According to the latest global cancer burden data released by the World Health Organization’s International Agency for Research on Cancer (IARC), in 2020, there will be 2.2 million new cases of lung cancer worldwide (only second only to breast cancer), and 1.8 million new lung cancer deaths in 2020 (much more than anyone else). cancer), it is worth noting that most lung cancer patients have a history of smoking, but 10%-20% of lung cancer patients have never smoked. In addition, women who never smoked were more likely to develop lung cancer, and earlier than smokers.

Environmental risk factors, such as exposure to secondhand smoke, radiation, air pollution and asbestos, or previous lung disease, may explain some of the causes of lung cancer in non-smokers, but until Now, scientists know what causes lung cancer in these nonsmokers.

On September 6, 2021, the National Cancer Institute (NCI) and several research institutions published an article titled “Nature Genetics”, a sub-journal of “Nature”. Research paper on “The Genome and Evolutionary Classification of Lung Cancer in Never-Smokers.”

This study analyzed the genomes of non-smoking lung cancer patients and found that the majority of non-smoking lung cancers are caused by genetic mutations that accumulate through the body’s natural processes and are the first A description of three molecular subtypes of lung cancer in never-smokers – ‘piano’, ‘mezzo-forte’ and ‘forte’. These findings will help unravel the secrets of lung cancer in never-smokers and may guide the development of more precise clinical treatments.

In this large epidemiological study, researchers sequenced the whole genome of 232 non-smoking lung cancer patients, mostly of European descent, and compared their genetic differences between tumor tissue and normal tissue to characterize genomic changes in tumor tissue.

The tumor types in these lung cancer patients included 189 adenocarcinomas (the most common type of lung cancer), 36 squamous cell carcinomas, and seven other different types of tumors. These patients had no previous cancer treatment during the study period.

Whole-genome sequencing analysis of lung cancer in never-smokers

Next, the researchers sorted out Mutational signature of tumor genomes in smoking lung cancer patients.

A mutational signature is a mutational pattern associated with a specific mutational process, such as damage caused by the body’s natural activities (eg, DNA repair defects or oxidative stress) or exposure to carcinogens.

Mutational signals are like archives of tumor activity, leading to the accumulation of mutations that provide clues to cancer development.

They found that the majority of tumor genomes in never-smokers had mutational signatures associated with impairment of endogenous processes, which are natural processes that occur in the body.

As expected, because the study was limited to people who never smoked, the researchers did not find any mutational signatures previously associated with direct tobacco exposure.

In addition, they did not find these characteristics in the 62 patients exposed to secondhand smoke.

However, further research is needed to confirm this, given the small sample sizes of the studies and the large variability in exposure.

Lung cancer in non-smokers is caused by genetic mutations that accumulate during natural processes in the body

Not only that, but the genomic analysis revealed three new molecular subtypes of lung cancer in never-smokers, which the researchers named based on the level of changes in the tumor’s genome.

The “piano” (music term: weak) subtype has the fewest mutations and appears to be associated with stem cell activation, tumors in this subtype grow very slowly, often over many years, and It is difficult to treat because it can have many different driver mutations.

The “mezzo-forte” subtype has specific chromosomal changes as well as a mutation in the growth factor receptor gene EGFR, a common type of mutation in lung cancer that results in faster tumor growth .

The “forte” (musical term: strong) subtype exhibits genome-wide doubling, a genomic change common in lung cancer in smokers, and the Tumors also grew rapidly.

Genomic analysis reveals three molecular subtypes of lung cancer in never-smokers

Corresponding author, Epidemiology Scientist Dr Maria Teresa Landi said: “What we are seeing is that there are distinct subtypes of lung cancer in never-smokers with different molecular features and evolutionary processes. In the future, we may have different subtypes based on these subtypes. treatment.”

More importantly, the findings will guide the development of lung cancer prevention and treatment methods for non-smokers.

For example, the slow-growing piano subtype could provide clinicians with a window of opportunity for early detection of these difficult-to-treat tumors.

In contrast, the rapidly developing mezzo-forte and forte subtypes have only a few major driver mutations, suggesting that these tumors can be identified by a single biopsy and can be derived from the target benefit from treatment.

Prophylaxis and targeted therapy based on the molecular characteristics of these subtypes

Maria Teresa Landi, Ph.D., said, Future research directions are to expand the study sample to include people of different ethnic backgrounds and geographic locations, and to have a well-characterized risk factor for their lung cancer exposure history. “We are just beginning to understand how these tumors evolve, and our analysis shows that lung cancer is heterogeneous and diverse in people who have never smoked.”

https://www.nature.com/articles/s41588-021-00920-0

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