Why Do Most Smokers Never Get Lung Cancer, According to DNA Mutation Research

 

        Despite the fact that cigarette smoking is the leading cause of lung cancer, only a small percentage of smokers develop the disease. Some smokers may have robust systems that protect them from lung cancer by restricting mutations, according to a study headed by academics at Albert Einstein College of Medicine and published online on April 11, 2022 in Nature Genetics. The findings could assist identify smokers who are at a higher risk of developing the condition and should be closely monitored.

"This could be a significant step toward lung cancer risk prevention and early detection, moving away from the current herculean efforts needed to combat late-stage disease, where the majority of health expenditures and misery occur," said Simon Spivack, M.D., M.P.H., a co-senior author of the study, professor of medicine, epidemiology & population health, and genetics at Einstein, and a pulmonologist at Montefiore Health System.

                        Overcoming Challenges in Cell Mutation Research 

        Smoking has long been thought to cause lung cancer by causing DNA abnormalities in normal lung cells. Jan Vijg, Ph.D., a study co-senior author and professor and chair of genetics, professor of ophthalmology and visual sciences, and the Lola and Saul Kramer Chair in Molecular Genetics at Einstein, said, "But that could never be proven until our study because there was no way to accurately quantify mutations in normal cells" (also at the Center for Single-Cell Omics, Jiaotong University School of Medicine in Shanghai, China). Dr. Vijg overcome this challenge a few years ago when he developed a better method for sequencing the whole genomes of individual cells.

When studying cells with rare and random mutations, single-cell whole-genome sequencing technologies might generate sequencing errors that are difficult to identify from real mutations, which is a major problem. Dr. Vijg came up with a new sequencing technology called single-cell multiple displacement amplification to overcome the problem (SCMDA).

The Einstein researchers utilised SCMDA to analyse the mutational landscape of normal lung epithelial cells (cells that line the lungs) from two groups of people: 14 never-smokers ranging in age from 11 to 86, and 19 smokers ranging in age from 44 to 81 and having smoked a total of 116 pack years. (One pack year is one pack of cigarettes smoked every day for a year.) The cells were taken from people who were having a bronchoscopy for a reason other than malignancy. “These lung cells survive for years, even decades, and thus can accumulate mutations with both age and smoking,” said Dr. Spivack. "Of all the cell types in the lungs, these are the ones that are most prone to turn malignant."

Mutations Caused by Smoking

The researchers discovered that mutations (single-nucleotide variations and minor insertions and deletions) accumulated in the lung cells of nonsmokers as they grew older, and that smokers' lung cells had considerably more mutations. Dr. Spivack stated, "This experimentally demonstrates that smoking increases lung cancer risk by increasing the frequency of mutations, as previously hypothesised." “This is likely one reason why so few non-smokers get lung cancer, while 10% to 20% of lifelong smokers do.”

The number of cell mutations discovered in lung cells grew in a straight line with the number of pack years of smoking, implying that the risk of lung cancer increased as well. However, after 23 pack years of exposure, the increase in cell mutations came to a halt.

“The heaviest smokers did not have the highest mutation burden,” said Dr. Spivack. "Our findings show that these people survived so long despite their severe smoking because they were able to prevent additional mutation accumulation." This leveling off of mutations could stem from these people having very proficient systems for repairing DNA damage or detoxifying cigarette smoke.”