June 18, 2024

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Why do most smokers not get lung cancer?

Why do most smokers not get lung cancer?


Why do most smokers not get lung cancer?

It is well known that lung cancer is closely related to smoking, and chemical carcinogens in cigarette smoke, such as polycyclic aromatic hydrocarbons (PAHs), can cause DNA damage and lead to cancer-causing mutations.


However, according to reports, 70% of smoking-related deaths occur in the elderly, and 80-90% of life-long smokers have never developed lung cancer, which means that about 10%-20% of life-long smokers develop lung cancer.


So why is there such a result? Perhaps it is more convincing to explain these observations from the perspective of molecular and genetic mechanisms, but comprehensive molecular risk assessment studies are still lacking.


Therefore, a research team led by Jan Vijg, Simon D Spivack and Zhenqiu Huang at the Albert Einstein College of Medicine took this problem a step further.

They used the single-cell multiple displacement amplification (SCMDA) technique to conduct a near-term study of 33 subjects aged 11-86 with smoking history ranging from never to 116 pack-years.

The terminal bronchial basal cells (proximal bronchial basal cells, PBBCs) were subjected to single-cell whole-genome sequencing, and the results were published in Nature Genetics (IF: 41.307).


Findings showed that the frequencies of single-nucleotide variants (SNVs) and insertions and deletions (INDELs) increased with age in never smokers and mutations in smokers frequency increased significantly.

When compared to smoking-years, mutations increased linearly with cancer risk until approximately 23 pack-years (ie, packs smoked per day × years of smoking) when mutation frequency plateaued.

The plateau in mutation frequency may be due to a more robust DNA damage repair system in this population, or the ability to detoxify tobacco smoke.


Why do most smokers not get lung cancer?
Screenshot of the homepage of the paper Source: Nature Genetics


Next, let’s take a look at how this research was carried out.



Mutation frequency and mutation spectrum of single nuclei

To characterize mutations, 33 subjects (19 smokers and 14 never smokers) were included in the study and their PBBCs were obtained.

Of the 19 smokers, 14 were diagnosed with lung cancer, compared with only 1 never-smoker.

The researchers isolated nuclei from frozen PBBCs pellets and determined the mutation frequency and mutation spectrum of 3-8 individual nuclei.


Why do most smokers not get lung cancer?

Schematic illustration of isolation, processing and analysis of PBBCs from human lung Source: Nature Genetics



Age-associated mutation accumulation in never-smoker PBBCs


To investigate the relationship between age and mutation frequency in PBBCs, we quantified somatic mutations, including single nucleotide variants (SNVs) and insertions and deletions (INDELs), in single PBBC ​​nuclei from never-smokers, And corrected for genome coverage and detection sensitivity.


The study found that the median number of SNVs per nucleus varied between 464 ± 108 (11 years) and 2739 ± 778 (86 years), equivalent to 28 mutations per cell per year (P = 3.9 × 10 −3 ) .

In addition, the investigators found that subjects’ median INDEL per nucleus increased with age, from 59 ± 18 (11 years old) to 304 ± 94 (86 years old), equivalent to approximately INDEL per cell per year 2 INDELs (P = 0.28).



Mutation frequency of PBBCs in smokers


Next, the researchers studied the accumulation of mutations with age in the PBBCs of smokers.

Similar to never-smokers, the mutation frequency in cells of smokers increased with age at a significantly higher rate, estimated at 91 SNVs per cell per year (P = 3.5 × 10−2 ), 63 more SNVs than never smokers (P = 2.1× 10 −2 ).


For INDELs, a significant increase in mutation frequency with age was observed in all subjects (P = 4.8 × 10 −2 ).

However, smokers aged 44 to 81 years had a higher frequency of INDELs compared with never smokers of the same age, but this was not statistically significant (P = 0.51).


Why do most smokers not get lung cancer?Mutation accumulation in PBBCs of smokers Source: Nature Genetics


To better understand the relationship between smoking and mutation burden, we analyzed mutation frequency in normal PBBCs as a function of cumulative smoking dose, expressed in self-reported pack-years, defined as 20 cigarettes per day for one year.


We modeled mutation frequency as a function of pack-years, using a negative binomial mixed-effects model.

In the absence of outliers, mutation frequency increased linearly up to 23 pack-years (95% CI: 10-51 pack-years) and then remained constant .

The results showed that heavy smokers (>60 pack-years) had no higher mutation frequency of PBBCs than moderate smokers (20.1-60 pack-years) (P = 0.11) .


Why do most smokers not get lung cancer?

Source of model for testing the relationship between mutation frequency and pack-years of smoking: Nature Genetics


Applying the same method to INDEL, the researchers found the same point of change at 23 pack-years.

The loss of this dose-response relationship in heavier smokers seems to suggest that cumulative mutations alone do not fully explain the increase in lung cancer risk with pack-years.


In addition to the effects of age and pack-years, they investigated the possible effect of smoking cessation (years abstained) on mutation frequency, but smoking cessation had no significant effect on SNV (P = 0.22) or INDEL (P = 0.76) frequency.


A, B: INDEL mutation frequency and smoking dose C, D: Effect of smoking cessation on mutation frequency
Source: Nature Genetics




Cancer driver mutations

Although somatic mutations are often random, they can amplify based on selective advantage over the host cell, a process that has been well-documented in cancer research.

Therefore, we further analyzed datasets of somatic mutations in known lung and pan-cancer driver genes.

100,656 somatic mutations were observed in nuclei from smokers and non-smokers, including 21 mutations in lung cancer driver genes in 11% of nuclei and 111 mutations in pan-cancer driver genes in 50% of nuclei.

However, permutation tests of random genomes showed no statistically significant enrichment for mutations in lung cancer (P = 0.73) or pan-cancer (P = 0.81) driver genes.


Cancer driver gene mutations in the nucleus of normal PBBCs Source: Nature Genetics



Mutational features

Next, the researchers analyzed somatic mutation signatures associated with aging or smoking.

Analysis of single base substitution (SBS) signatures found in smoker PBBCs revealed the presence of SBS4, whereas SBS4 was almost absent in never smokers .

SBS4 has previously been shown to be a major feature of lung cancer in smokers. Although the number of mutations in SBS4 was significantly higher in smokers, it was independent of age (P = 0.40).

Mutations caused by SBS5 were significantly associated with smoking status, but the association was stronger with chronological age.

The other 14 features extracted from all subjects, smokers and never smokers were associated with various molecular mechanisms.


Variation traits and smoking map source: Nature Genetics



Lung cancer susceptibility linked to germline genetic variation

Finally, to assess the possible influence of genetic background on mutations in PBBCs, we tested all subjects for germline variants previously associated with solid cancers and listed in the Clinvar database. Of the 31 subjects, 16 were diagnosed with cancer (14 lung cancer, 1 prostate cancer, 1 breast cancer).

They also found that a total of 17 people carried at least one of six identified genetic mutations associated with risk for solid cancers (lung, breast, colon, sarcoma, lymphoma, prostate).

Of these 17 subjects, 13 were diagnosed with cancer (11 lung cancer, 1 prostate cancer, and 1 breast cancer).


The investigators found that two smoking subjects had a polymorphism in the gene AKR1C2 (encoding aldehyde/ketone reductase), which is critical for the detoxification of PAHs, and that the SBS4-characteristic portion of the mutational burden was more than 2-fold increased in these two subjects (P=2.2×10−16).

This suggests that AKR1C2 mutations may reduce the detoxification of tobacco smoke and increase susceptibility to smoking-induced mutagenicity in carriers.


Source of germline genetic variation associated with solid cancers: Nature Genetics




In conclusion, this study analyzed the somatic mutations of human lung single cells in smokers and non-smokers of different ages, and confirmed the model that smoking increases the risk of lung cancer by increasing the frequency of somatic mutations.

Through this model, it is reasonable to explain why large Most smokers never get lung cancer.


On the other hand, the dose-dependence of gene mutation frequency in smokers plateaued after 23 pack years, suggesting that lung cancer risk can be reduced by reducing mutations, for example by improving DNA repair accuracy or by optimizing the detoxification of tobacco smoke. 


This study provides a rationale for further evaluation of the nature of intrinsic lung cancer risk factors that modulate susceptibility to mutations in normal bronchial cells.





Why do most smokers not get lung cancer?

(source:internet, reference only)

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