Study suggests why most smokers don't get lung cancer

Date:
April 11, 2022
Source:
Albert Einstein College of Medicine
Summary:
Cigarette smoking is overwhelmingly the main cause of lung cancer,
yet only a minority of smokers develop the disease. A study suggests
that some smokers may have robust mechanisms that protect them
from lung cancer by limiting mutations. The findings could help
identify those smokers who face an increased risk for the disease
and therefore warrant especially close monitoring.



FULL STORY ========================================================================== Cigarette smoking is overwhelmingly the main cause of lung cancer, yet
only a minority of smokers develop the disease. A study led by scientists
at Albert Einstein College of Medicine and published online today in
Nature Genetics suggests that some smokers may have robust mechanisms
that protect them from lung cancer by limiting mutations. The findings
could help identify those smokers who face an increased risk for the
disease and therefore warrant especially close monitoring.


========================================================================== "This may prove to be an important step toward the prevention and early detection of lung cancer risk and away from the current herculean
efforts needed to battle 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, of epidemiology & population health, and of genetics at Einstein, and a pulmonologist at Montefiore Health System.

Overcoming Obstacles to Study Cell Mutations It's long been assumed that smoking leads to lung cancer by triggering DNA mutations in normal lung
cells. "But that could never be proven until our study, since there was
no way to accurately quantify mutations in normal cells," said 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 (also at the Center for Single-Cell Omics, Jiaotong University School of Medicine in Shanghai,
China).

Dr. Vijg overcame that obstacle a few years ago by developing an improved method for sequencing the entire genomes of individual cells.

Single-cell whole-genome sequencing methods can introduce sequencing
errors that are hard 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). As reported in Nature
Methods in 2017, this method accounts for and reduces sequencing errors.

The Einstein researchers used SCMDA to compare the mutational landscape
of normal lung epithelial cells (i.e., cells lining the lung) from two
types of people: 14 never-smokers, ages 11 to 86; and 19 smokers, ages
44 to 81, who had smoked a maximum of 116 pack years. (One pack year of
smoking equals 1 pack of cigarettes smoked per day for one year.) The
cells were collected from patients who were undergoing bronchoscopy for diagnostic tests unrelated to cancer.

"These lung cells survive for years, even decades, and thus can accumulate mutations with both age and smoking," said Dr. Spivack. "Of all the
lung's cell types, these are among the most likely to become cancerous." 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 age -- and that significantly more mutations were found in the lung
cells of the smokers. "This experimentally confirms that smoking increases
lung cancer risk by increasing the frequency of mutations, as previously hypothesized," said Dr. Spivack. "This is likely one reason why so few non-smokers get lung cancer, while 10% to 20% of lifelong smokers do."
Another finding from the study: The number of cell mutations detected in
lung cells increased in a straight line with the number of pack years
of smoking - - and, presumably, the risk for lung cancer increased as
well. But interestingly, the rise in cell mutations halted after 23 pack
years of exposure.

"The heaviest smokers did not have the highest mutation burden," said Dr.

Spivack. "Our data suggest that these individuals may have survived for
so long in spite of their heavy smoking because they managed to suppress further mutation accumulation. This leveling off of mutations could stem
from these people having very proficient systems for repairing DNA damage
or detoxifying cigarette smoke." The finding has led to a new research direction. "We now wish to develop new assays that can measure someone's capacity for DNA repair or detoxification, which could offer a new way
to assess one's risk for lung cancer," said Dr.

Vijg.

The study is titled, "Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking." Additional Einstein authors include: Zhenqiu Huang, Ph.D., Shixiang Sun, Ph.D.,
Moonsook Lee, M.S., Yakov Peter, Ph.D., Ali Sadoughi, M.D., Chirag Shah,
M.D., and Kenny Ye, Ph.D., Miao Shi, Ph.D., Spencer Waldman, B.S.,
Ava Marsh, B.A., Taha Siddiqui, M.B.B.S., Alexander Y. Maslov, M.D.,
Ph.D. (also at Voronezh State University of Engineering Technology,
Voronezh, Russia), and Xiao Dong, Ph.D.

(also at University of Minnesota, Minneapolis MN).

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


========================================================================== Story Source: Materials provided by
Albert_Einstein_College_of_Medicine. Note: Content may be edited for
style and length.


========================================================================== Journal References:
1. 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, Jan
Vijg. Single-cell analysis of somatic mutations in human bronchial
epithelial cells in relation to aging and smoking. Nature Genetics,
2022; DOI: 10.1038/ s41588-022-01035-w
2. Xiao Dong, Lei Zhang, Brandon Milholland, Moonsook Lee, Alexander Y
Maslov, Tao Wang, Jan Vijg. Accurate identification of
single-nucleotide variants in whole-genome-amplified single
cells. Nature Methods, 2017; 14 (5): 491 DOI: 10.1038/nmeth.4227 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220411113733.htm

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