A genomic analysis of lung cancer in people without a history of smoking has found that most of these tumors arise from the accumulation of mutations caused by natural processes in the body, according to the researchers published in the journal ‘ Nature Genetics ‘.
This study was conducted by an international team led by researchers from the National Cancer Institute (NCI), part of the National Institutes of Health (NIH) of the United States, and describes for the first time three molecular subtypes of lung cancer in people who they have never smoked.
These insights will help unravel the mystery of how lung cancer arises in people without a history of smoking and may guide the development of more precise clinical treatments.
“What we are seeing is that there are different subtypes of lung cancer in never smokers that have different molecular characteristics and evolutionary processes,” explains epidemiologist Maria Teresa Landi, of the Branch of Integrative Tumor Epidemiology in the Division of Epidemiology and Genetics of the NCI, who led the study. “In the future we may have different treatments based on these subtypes.”
Lung cancer is the leading cause of cancer death worldwide. Every year more than 2 million people around the planet are diagnosed with the disease. Most of those who develop lung cancer have a history of smoking, but between 10% and 20% have never smoked and that lung cancer in those who have never smoked occurs more frequently in women and at a later age earlier than lung cancer in smokers.
Environmental risk factors, such as exposure to second-hand smoke, radon, air pollution, and asbestos, or previous lung disease, may explain some lung cancers among never-smokers, but scientists have not yet they know what causes most of these cancers.
In this large epidemiological study, researchers used whole genome sequencing to characterize genomic changes in tumor tissue and corresponding normal tissue of 232 non-smokers, predominantly of European descent, who had been diagnosed with lung cancer from not small cells. 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.
The researchers examined tumor genomes for mutational signatures, which are patterns of mutations associated with specific mutational processes, such as damage caused by natural activities of the body (for example, defective DNA repair or oxidative stress) or by exposure to carcinogens.
Mutational signatures act as a tumor archive of the activities that led to the accumulation of mutations, providing clues to the cause of cancer development. There is currently a catalog of known mutational signatures, although some have no known cause. In this study, the researchers found that the majority of the genomes of tumors that had never smoked had mutational signatures associated with damage produced by endogenous processes , that is, natural processes that occur within the body.
Unsurprisingly, since the study was limited to never smokers, the researchers did not find any mutational signatures that had previously been associated with direct exposure to smoking . They also did not find such signatures among the 62 patients who had been exposed to second-hand smoke. However, Dr. Landi cautions that because the sample size was small, a larger sample “with detailed exposure information is required to really study the impact of passive smoking on the development of lung cancer in non-smokers.”
Genomic analyzes also revealed three new lung cancer subtypes in nonsmokers, which the researchers assigned musical names based on the level of “noise” (that is, the number of genomic changes) in the tumors.
The predominant subtype ‘piano’ was the one with the fewest mutations; it seemed to be associated with the activation of progenitor cells, which participate in the creation of new cells. This tumor subtype grows very slowly , over many years, and is difficult to treat because it can have many different driver mutations.
The ‘mezzo-forte’ subtype had specific chromosomal changes, as well as mutations in the EGFR growth factor receptor gene, which is usually altered in lung cancer, and showed faster tumor growth. Finally, the ‘forte’ subtype exhibited a genome-wide duplication, a genomic change commonly seen in lung cancers from smokers. This tumor subtype also grows rapidly.
“We are beginning to distinguish subtypes that might have different approaches to prevention and treatment,” explains Landi. For example, the slow-growing piano subtype could 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 have only a few major mutations, suggesting that these tumors could be identified with a single biopsy and benefit from targeted treatments , he adds.
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 at the beginning of understanding how these tumors evolve,” says Landi. “This analysis shows that there is heterogeneity , or diversity, in lung cancers in never smokers.”
Dr. Stephen J. Chanock, director of the NCI Division of Cancer Epidemiology and Genetics, has expressed his confidence that “this detective-style research on the genomic characteristics of tumors opens new avenues of discovery for multiple types of cancer.”