DNA 돌연변이 연구는 대부분의 흡연자가 폐암이 되지 않는 이유를 밝혀


흡연 폐암의 그림

흡연은 압도적으로 폐암의 주된 원인이지만, 흡연자의 소수만이이 질병을 발병합니다.앨버트 아인스타인 의과대학의 과학자가 주도하고 2022년 4월 11일에 온라인으로 공개된 연구 네이처 제네틱스 일부 흡연자는 돌연변이를 제한함으로써 폐암으로부터 그들을 보호하는 강력한 메커니즘을 가질 수 있음을 시사합니다. 조사 결과는 질병의 위험이 높은 것에 직면하는 흡연자를 확인하는 데 도움이 될 수 있으므로 특히 면밀한 모니터링이 필요합니다.

“이것은 폐암 위험 예방과 조기 발견을 위한 중요한 단계이며, 의료비와 비참함의 대부분이 발생하는 후기 질환과 싸우는 데 필요한 현재의 대담한 노력에서 벗어난다는 것을 증명한다. “일지도 모릅니다.”라고 사이먼 스피백 의학 박사는 말했다. , MPH, 연구 공동 주임 저자, 의학, 역학 및 인구 건강, 아인슈타인 유전학 교수, 그리고 몬테피오레 헬스 시스템의 호흡기과 의사.

사이먼 스피백

Simon Spivack, MD, MPH 공동 주임 저자. 크레딧: Albert Einstein College of Medicine

세포 돌연변이를 연구하는 장애를 극복

흡연은 방아쇠를 당겨 폐암으로 이어질 것으로 오랫동안 생각해 왔습니다.[{” attribute=””>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.”

Jan Vijg

Jan Vijg, Ph.D. Co-senior 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 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.

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, 11 April 2022, Nature 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.” 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).



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