Nature Genetics: Why don't most smokers get lung cancer?

According to the World Health Organization's International Agency for Research on Cancer (IARC) 2020 global cancer burden data, lung cancer is the second most common cancer worldwide (2.

Smoking is the leading cause of the vast majority of lung cancers, yet only a minority of smokers develop lung cancer.

Using single-cell sequencing technology, the study found that some of the most smokers may have powerful "self-protection mechanisms" that limit the DNA mutations caused by smoking to protect themselves from lung cancer

Smoking has long been thought to cause lung cancer through smoke-induced DNA mutations in normal cells

There are some sequencing errors during single-cell whole-genome sequencing that are difficult to distinguish from true DNA mutations, especially when analyzing rare or random mutations

In 2017, Professor Jan Vijg's team published a research paper entitled: Accurate identification of single-nucleotide variants in whole-genome-amplified single cells in the journal Nature Methods

In this latest study, the research team used the single-cell multiple displacement amplification (SCMDA) technique to analyze and compare DNA mutations in normal lung epithelial cells from two populations, one from never-smokers (a total of 14 people, aged between 11-83 years old), one is a smoker (19 people in total, aged 44-81 years), these smokers smoke up to 116 pack-years (1 pack-year refers to the number of packs smoked per day × the number of years of smoking; for example Smoking 2 packs a day for 20 years, or 40 pack-years), 14 of the 19 smokers developed lung cancer, and 1 of the 14 non-smokers developed lung cancer

The lung cells used for sequencing were collected from patients undergoing bronchoscopy for diagnostic tests not related to cancer

The researchers found that DNA mutations (single-nucleotide variations and insertions and deletions of small DNA fragments) accumulate in the lung cells of non-smokers and smokers with age.

The above findings confirm that smoking increases lung cancer risk by increasing DNA mutations, revealing why few nonsmokers get lung cancer, while 10%-20% of lifetime smokers get lung cancer

But it also raises the question: Why don't most smokers get lung cancer?

The team found that the number of DNA mutations detected in lung epithelial cells increased linearly with the number of pack-years smoked, which led to an increased risk of lung cancer

That is, those who smoked the most did not have a corresponding increase in their DNA mutation burden to the highest levels

Dr.

Professor Jan Vijg, the study's co-corresponding author, said the discovery led to a new direction of research to assess a person's lung cancer risk by testing his DNA repair or detoxification abilities

Original source:

Huang, Z.