The majority of lung cancer tumors in persons who have never smoked are generated by the accumulation of mutations induced by natural processes in the body, according to a genomic analysis of lung cancer in people who have never smoked.
This study, headed by researchers at the National Cancer Institute (NCI), which is part of the National Institutes of Health (NIH), reveals three molecular subtypes of lung cancer among persons who have never smoked for the first time.
These findings may aid in the unraveling of the enigma of how lung cancer develops in those who have never smoked, as well as the creation of more specific therapeutic therapies. Nature Genetics released the findings today (September 6, 2021).
“What we’re seeing is that there are several subtypes of lung cancer among never smokers, each with its own molecular characteristics and evolutionary processes,” said epidemiologist Maria Teresa Landi, M.D., Ph.D., of the NCI’s Division of Cancer Epidemiology and Genetics, who led the study. “We may be able to offer various therapies based on these subgroups in the future.”
Lung cancer is the most common cancer-related mortality in the world. More than 2 million people are diagnosed with the illness each year all around the world. The majority of people who get lung cancer have smoked tobacco in the past, while 10% to 20% of people who develop lung cancer have never smoked. Lung cancer in nonsmokers is more common in women and develops at a younger age than lung cancer in smokers.
Some lung cancers among never smokers may be explained by environmental risk factors such as secondhand cigarette smoke, radon, air pollution, and asbestos, as well as having had previous lung illnesses, but scientists still don’t know what causes the bulk of these malignancies.
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The researchers employed whole-genome sequencing to analyze genetic alterations in tumor tissue and matched normal tissue from 232 never smokers, mostly of European origin, who had been diagnosed with non-small cell lung cancer in this major epidemiologic study. 189 adenocarcinomas (the most prevalent kind of lung cancer), 36 carcinoids, and seven additional tumors of various sorts were among the tumors. The cancer patients had not yet received any therapy.
The researchers looked for mutational signatures in tumor genomes, which are patterns of mutations linked to specific mutational processes, such as damage caused by normal bodily processes (such as poor DNA repair or oxidative stress) or exposure to carcinogens. Mutational signatures serve as a record of the events that lead to the accumulation of mutations in a tumor, revealing information about what caused the cancer to grow.
Although some signatures have no known cause, there is currently a library of known mutational signatures. The researchers observed that a majority of the tumor genomes of never smokers had mutational fingerprints linked to damage caused by endogenous processes, or natural processes that occur inside the body.
Because the study only included never smokers, the researchers did not identify any mutational markers previously linked to tobacco smoking. Those markers were also not found among the 62 patients who had been exposed to secondhand cigarette smoke. Dr. Landi noted, however, that the sample size was tiny and the exposure amount was very varied.
“To truly examine the influence of secondhand cigarette smoking on the development of lung cancer in never smokers, we need a bigger sample size with precise information on exposure,” Dr. Landi stated.
The genomic studies also identified three new subtypes of lung cancer among never smokers, which the researchers named after the amount of “noise” (that is, the number of genetic alterations) in the tumors. The most mutations were found in the prominent “piano” subtype, which appeared to be linked to the activation of progenitor cells, which are involved in the production of new cells.
Because it might have a variety of driving mutations, this kind of tumor develops slowly over many years and is difficult to cure. The “mezzo-forte” subtype demonstrated quicker tumor development and contained unique chromosomal alterations as well as mutations in the growth factor receptor gene EGFR, which is often changed in lung cancer. Whole-genome doubling was found in the “forte” subtype, a genetic alteration that is common in smokers’ lung malignancies. This sort of tumor develops fast as well.
“We’re starting to differentiate subgroups that may require different preventative and therapy approaches,” Dr. Landi explained. The slow-growing piano variety, for example, may provide physicians with a window of opportunity to diagnose these tumors sooner, when they are easier to cure. The mezzo-forte and forte subtypes, on the other hand, contain only a few significant driver mutations, implying that these cancers might be detected with a single biopsy and treated with targeted therapies, she added.
A future focus of this research will be on persons from various ethnic origins and geographical areas who have a well-documented history of exposure to lung cancer risk factors.
Dr. Landi explained, “We’re only beginning to grasp how these cancers develop.” “This study demonstrates that lung tumors in never smokers have heterogeneity, or diversity.”