DNA Mutation Research Reveals Why Most Smokers Never Get Lung Cancer


Smoking is the main cause of lung cancer, but only a minority of smokers develop the disease. A study conducted by scientists at the Albert Einstein College of Medicine and published online April 11, 2022, in Natural genetics suggests that some smokers may have robust mechanisms that protect them from lung cancer by limiting mutations. The results could help identify smokers who face an increased risk of contracting the disease and therefore warrant particularly close monitoring.

“This may prove to be an important step towards the prevention and early detection of lung cancer risk and away from the current Herculean efforts needed to tackle the disease at an advanced stage, where the majority of healthcare expenditure occurs and misery,” said Simon Spivack, MD. , MPH, study co-lead author, professor of medicine, epidemiology and population health, and genetics at Einstein, and pulmonologist at Montefiore Health System.

Simon Spivack

Simon Spivack, MD, MPH Study co-lead author. Credit: Albert Einstein College of Medicine

Overcoming obstacles to study cellular mutations

It has long been assumed that smoking leads to lung cancer by triggering DNA

DNA, or deoxyribonucleic acid, is a molecule composed of two long strands of nucleotides that coil around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth, and reproduction. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).
” data-gt-translate-attributes=”[{” attribute=””>DNA mutations in normal lung cells. “But this could never be proven before our study, because there was no way to accurately quantify mutations in normal cells,” said co-lead author Jan Vijg, Ph.D. study and professor and holder of the chair of genetics, professor of ophthalmology. and visual sciences, and the Lola and Saul Kramer Professorship in Molecular Genetics at Einstein (also at the Center for Single-Cell Omics at Jiaotong University School of Medicine in Shanghai, China). Dr. Vijg overcame this hurdle a few years ago by developing an improved method for sequencing whole genomes of single cells.

Whole-genome single-cell sequencing methods can introduce sequencing errors that are difficult to distinguish from true mutations, a serious flaw when analyzing cells containing rare and random mutations. Dr. Vijg solved this problem by developing a new sequencing technique called single-cell multiple displacement amplification (SCMDA). Like reported in Natural methods in 2017, this method counts and reduces sequencing errors.

The Einstein researchers used SCMDA to compare the mutational landscape of normal lung epithelial cells (i.e. the cells lining the lungs) of two types of people: 14 never-smokers, ages 11-86; and 19 smokers, ages 44 to 81, who had smoked a maximum of 116 pack-years. (A pack-year of smoking is equivalent to 1 pack of cigarettes smoked a day for a year.) The cells were taken from patients undergoing bronchoscopy for diagnostic tests unrelated to cancer. “These lung cells survive for years, even decades, and therefore can accumulate mutations with age and smoking,” Dr. Spivack said. “Of all the types of lung cells, these are among the most likely to become cancerous.”

Jan Vijg

Jan Vijg, Ph.D. Co-lead author of the study. Credit: Albert Einstein College of Medicine

Mutations caused by smoking

The researchers found that mutations (single nucleotide variants and small insertions and deletions) accumulated in the lung cells of non-smokers as they aged, and that many more mutations were found in the lung cells of non-smokers. smokers. “This experimentally confirms that smoking increases lung cancer risk by increasing mutation frequency, as previously hypothesized,” Dr. Spivack said. “That’s probably one of the reasons why so few non-smokers get lung cancer, while 10-20% of lifelong smokers have it.”

Another finding from the study: the number of cellular mutations detected in lung cells increased in a straight line with the number of pack-years of smoking – and, presumably, the risk of lung cancer also increased. But interestingly, the increase in cellular mutations stopped after 23 pack years of exposure.

“The heaviest smokers did not have the highest mutation burden,” Dr. Spivack said. “Our data suggest that these people may have survived so long despite their heavy tobacco use because they were able to suppress the accumulation of mutations. This leveling of mutations could be due to the fact that these people have very efficient systems to repair DNA damage or detoxify cigarette smoke.

The discovery led to a new direction of research. “We now want to develop new tests that can measure a person’s ability to repair or detoxify DNA, which could offer a new way to assess their risk of lung cancer,” said Dr. Vijg.

Reference: “Single Cell Analysis of Somatic Mutations in Human Bronchial Epithelial Cells in Relation to Aging and Smoking” by Zhenqiu Huang, Shixiang Sun, Moonsook Lee, Alexander Y. Maslov, Miao Shi, Spencer Waldman, Ava Marsh, Taha Siddiqui, Xiao Dong, Yakov Peter, Ali Sadoughi, Chirag Shah, Kenny Ye, Simon D. Spivack and Jan Vijg, April 11, 2022, Natural genetics.
DOI: 10.1038/s41588-022-01035-w

The study is titled “Single-Cell Analysis of Somatic Mutations in Human Bronchial Epithelial Cells in Relation to Aging and Smoking.” Other Einstein authors include: Zhenqiu Huang, Ph.D., Shixiang Sun, Ph.D., Moonsook Lee, MS, Yakov Peter, Ph.D., Ali Sadoughi, MD, Chirag Shah, MD and Kenny Ye, Ph.D., Miao Shi, Ph.D., Spencer Waldman, BS, Ava Marsh, BA, Taha Siddiqui, MBBS, Alexander Y. Maslov, MD, Ph.D. (also at State University of Technology of Voronezh Engineering, Voronezh, Russia) and Xiao Dong, Ph.D. (also at the University of Minnesota, Minneapolis MN).

This study was supported by grants from the National Institutes of Health (U01 ES029519-01, U01HL145560, AG017242, and AG056278).


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