NIH study illuminates origins of lung cancer in never smokers

NIH study illuminates origins of lung cancer in never smokers

A genomic examination of lung cancer in people who have never smoked discovered that the majority of these cancers develop as a result of the accumulation of mutations generated by natural bodily processes. This study, coordinated by researchers at the National Cancer Institute (NCI), a component of the National Institutes of Health (NIH), identifies for the first time three molecular subtypes of lung cancer among non-smokers.

These findings will contribute to unravelling the puzzle of how lung cancer develops in persons who have never smoked and will likely aid in the development of more specific clinical treatments. The findings were published in Nature Genetics on September 6, 2021.

“What we are seeing is that there are distinct subtypes of lung cancer in never smokers with distinct molecular characteristics and evolutionary processes,” said lead author Maria Teresa Landi, M.D., Ph.D., of the Integrative Tumor Epidemiology Branch in the National Cancer Institute's Division of Cancer Epidemiology and Genetics. “In the future, we may be able to differentiate between various subtypes of cancer.”

Lung cancer is the most common type of cancer and the main cause of cancer-related death worldwide. Each year, the condition is diagnosed in over 2 million people worldwide. While the majority of people who acquire lung cancer have a history of tobacco use, 10% to 20% of persons who develop lung cancer have never smoked. Never-smokers develop lung cancer at a higher rate and at a younger age than smokers.

Environmental risk factors such as exposure to secondhand cigarette smoke, radon, air pollution, and asbestos, as well as a history of lung illness, may account for some lung cancers in never smokers, but experts are still unsure of the source of the bulk of these malignancies.

The researchers used whole-genome sequencing to analyse the genetic changes in tumour tissue and matched normal tissue from 232 never-smokers, mostly of European ancestry, who were diagnosed with non-small cell lung cancer. 189 adenocarcinomas (the most frequent type of lung cancer), 36 carcinoids, and seven other types of tumours were identified. The patients had not yet received cancer treatment.

The researchers searched tumour genomes for mutational signatures, which are patterns of mutations linked with certain mutational processes, such as damage caused by normal bodily processes (for example, defective DNA repair or oxidative stress) or exposure to carcinogens. Mutational signatures serve as a record of the events leading up to the accumulation of mutations in a tumour, providing insight into what caused the cancer to emerge. Although some signatures have no known cause, a collection of known mutational signatures presently exists. The researchers discovered that the majority of never-smoker tumour genomes exhibited mutational fingerprints linked with damage caused by endogenous mechanisms, or natural processes occurring within the body.

As expected, given the study's restriction to never smokers, the researchers discovered no mutational markers previously associated with direct tobacco smoking exposure. They also did not discover such signs among the 62 patients exposed to secondhand tobacco smoke. Dr. Landi noted, however, that the sample size was tiny and the exposure amount was highly varied.

“We need a larger sample size and more thorough exposure data to truly evaluate the effect of secondhand cigarette smoking on the development of lung cancer in never smokers,” Dr. Landi added.

Additionally, the genomic analysis identified three distinct subtypes of lung cancer in nonsmokers, which the researchers named musically based on the amount of "noise" (that is, the number of genetic alterations) in the tumours. The main "piano" subtype had the fewest mutations; it appeared to be connected with the activation of progenitor cells, which are responsible for cell formation. This subtype of tumour grows exceedingly slowly over a long period of time and is difficult to treat due to the fact that it can harbour a variety of distinct driving mutations. The "mezzo-forte" subtype exhibited unique chromosomal abnormalities as well as alterations in the growth factor receptor gene EGFR, which is frequently changed in lung cancer. The "forte" subtype revealed whole-genome duplication, a common genetic alteration in smokers' lung tumours. Additionally, this form of tumour grows rapidly.

“We're beginning to differentiate categories that may require distinct approaches to prevention and treatment,” Dr. Landi explained. For instance, the slow-growing piano subtype may let clinicians to notice these tumours early, when they are easier to cure. In comparison, the mezzo-forte and forte subtypes contain a limited number of key driver mutations, implying that these cancers can be detected with a single biopsy and benefit from targeted therapy, she said.

A future objective of this research will be to examine individuals from diverse ethnic backgrounds and geographic places who have a well-documented history of exposure to lung cancer risk factors.

“We are only beginning to comprehend how these cancers evolve,” Dr. Landi explained. This data demonstrates that lung malignancies in never-smokers are heterogeneous, or diverse.”

“We anticipate that this detective-style analysis of genomic tumour traits will open new routes of discovery for numerous cancer types,” said Stephen J. Chanock, M.D., director of the National Cancer Institute's Division of Cancer Epidemiology and Genetics.