Who doesn't smoke…

Lung cancer in non-smokers was divided into three subtypes according to the nature of mutations

Vera Mukhina, N+1

By analyzing the complete genomes of tumors in non-smoking patients with lung cancer, scientists were able to divide them into three groups based on typical mutations and their number and confirm the characteristic differences in this disease in smokers and non-smokers. Understanding the nature of mutagenesis makes it possible to use appropriate approaches in treatment. The work was published in the journal Nature Genetics (Zhang et al., Genomic and evolutionary classification of lung cancer in never smokers).

Lung cancer is considered a disease of smokers, but in 10-25 percent of cases it occurs in people who have never smoked. In some cases, this can be explained by passive smoking, but often the nature of the disease and the resulting mutations are different, and the cause of the disease is apparently also different. Tobacco smoke contains dozens of carcinogens, the constant bombardment of which leads to the fact that a huge number of point mutations and larger genomic rearrangements such as doubling of individual genes, chromosomes and even the whole genome accumulate in lung cells. The more mutations, the greater the chance that one of them will trigger the formation of a tumor. In non-smokers, the appearance of inclusive mutations should be due to other reasons, and the mutation profile itself should look different. Nevertheless, most of the research is conducted with the participation of smokers, whereas for non-smokers there are only small samples of data on which it is difficult to draw global conclusions.

Tongwu Zhang from the American National Institute of Oncology and his colleagues described what the mutation profile usually looks like. The work was based on the data of 232 patients with lung cancer who had never smoked, mainly with adenocarcinoma, for whom paired samples from healthy tissue and tumors were collected and completely sequenced. Comparison with similar data on other cancers from the TCGA database showed that mutations accumulate in much smaller amounts in the tumors of non-smokers than in smokers. The set of the most popular mutations turned out to be standard – in half of the samples, mutations of the RAS signaling pathway genes were found mutually exclusive, such as mutations in EGFR (30.6 percent of cases), KRAS (7.3 percent) or others, and in another 15 percent of cases, breakdowns in the TP53 gene. The fact that these mutations practically did not occur together is explained by the fact that any of them is enough to provoke tumor growth.

Depending on the generative factor (for example, ultraviolet light or tobacco smoke), mutations can occur with different frequency in different parts of DNA, and by the predominance of certain mutations (for example, substitutions within CC by CA), the mutational signature of cancer can be restored. It turned out that there was no characteristic tobacco signature in the samples, although a quarter of patients said that they were regularly exposed to tobacco smoke.

Using clustering within a cohort of samples, it was possible to identify three subtypes that differ in the number and nature of changes in the genome. Approximately half of the cases were characterized by the absence of large genomic rearrangements, a low level of mutation accumulation and long telomeric regions indicating a relatively small number of cell divisions. There were few classical driver mutations that actually trigger oncogenesis, and those that were were mainly breakdowns in the genes responsible for laying chromatin. The researchers reconstructed the history of the origin of the tumor and suggested that they were formed most likely from stem cells that for some reason came out of a dormant state many years ago, and since then have been slowly dividing and accumulating mutations.

The researchers found the opposite situation – with full–genome duplications, rearrangements and a high level of accumulation of mutations - in 20 percent of cases. The nature of the rearrangements and frequent breakdowns of TP53 in this case are similar to those found in lung cancer of smokers. The tumor cells inside the samples are similar to each other, and the telomeres are short, which indicates a rapid rate of division after a recent driver mutation. Another 30 percent of the described cases occupy an intermediate position: there were separate genomic permutations like the doubling of chromosome arms and the average telomere length and the rate of accumulation of mutations, and EGFR mutations and RAS pathway genes turned out to be popular drivers in this subtype.

Mutations in the RAS and TRZ53 signaling pathway genes characteristic of patients of the second and third subgroups are associated with a poor prognosis in treatment and are difficult to correct, but a number of drugs are being developed for them now. For patients with the first subtype of lung cancer, they will most likely be ineffective, and they will need to look for other ways to treat them.

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