The mystery of the heavy smokers who never developed lung cancer finally elucidated?

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Smoking, the leading cause of cancer in the world, is a considerable risk factor for the disease, mainly lung cancer. Tobacco smoke notably caused mutations in lung cells – which multiplied abnormally during the formation of tumors. The risk would be multiplied by 10 or 15 for smokers (compared to non-smokers), but paradoxically, many “heavy smokers” would never develop cancer. Only a minority of smokers contract the disease: a real mystery for scientists. A new study published in the journal Natural genetics suggests that this difference is linked to complex genetic factors, from which some smokers are referred, and which protect against carcinogenic mutations.

Tobacco smoke can cause various harmful effects on lung cells. In the case of chronic obstructive pulmonary disease (COPD), for example, it irreversibly damages the progenitor cells of the lungs, preventing the renewal of destroyed functional cells. In the case of tumor formation, these cells renew and multiply excessively.

There are several forms of lung cancer. The most common tumors (80 to 85% of cases) are those called “non-small cell” (referring to the size of the tumor cells). They can form in the gland cells in the outer parts of the lungs. In this specific case, it is an adenocarcinoma.

In the same category is also squamous cell carcinoma, which usually develops in the cells of the bronchi and bronchioles, in the central parts of the lungs. There is also what is called large cell carcinoma, which can arise in any area of ​​the lungs. Other, rarer and no less serious forms of lung cancer include: (small cell lung cancer), soft tissue sarcoma, carcinoid, pleural mesothelioma.

Previous studies assumed that the excessive multiplication of lung cells during tumor formation was due to tobacco smoke-induced DNA mutations in healthy cells. The new study, conducted by researchers at the Albert Einstein College of Medicine (New York, USA) is the first to precisely quantify this mutation rate, thanks to a revolutionary and improved sequencing technique of the whole genomes of single cells. .

Thanks to this new technique, researchers may have finally discovered why not all smokers develop cancer, and especially why many heavy smokers never develop the disease. The findings could flow to new, more efficient and more targeted diagnostic methods, helping to identify smokers who face an accumulated risk of contracting the disease and who are at risk of particularly close surveillance.

This may prove to be an important step towards the prevention and early detection of lung cancer risk and a far cry from the current Herculean efforts needed to tackle the disease at a stage, where the majority of advanced healthcare expenditure occurs. “Said Simon Spivack, co-lead author of the study and professor of medicine, epidemiology and population health and genetics at the Albert Einstein College of Medicine.

A more accurate sequencing method

To quantify mutations in lung cells, the New York researchers developed a sequencing technique called single-cell multiple displacement amplification (SCMDA). Typical single-cell, whole-genome sequencing methods are notably quite limited in that errors can occur, which produce the true mutations that are difficult to identify. The new technique makes it possible to reduce the margins of error and to better detect rare and random mutations.

The mutational landscapes of the proximal bronchial basal cells of 33 individuals were then compared. 14 of them have never smoked and are aged 11 to 86, while the other 19, aged 44 to 81, have a maximum “smoking history” of 116 pack-years (PA) — 1 PA is equivalent to 1 pack of cigarettes smoked per day for one year. To give a concrete example, a person who has smoked 40 cigarettes a day for 40 years will have an AP of 2 (2 packets) x 40 = 80 AP.

Participants’ cells were removed by bronchoscopy. Proximal bronchial basal cells can survive for years or even decades and accumulate mutations with age that may be related to smoking. Moreover, of all the types of lung cells, they are among the most likely to become cancerous.

Results

The researchers’ first discovery was the accumulation of mutations in the lung cells of non-smokers. These mutations would accumulate with age and would be more numerous in smokers. ” This experimentally confirms that smoking increases the risk of lung cancer by increasing the frequency of mutations, as previously assumed. says Spivack. Moreover, the number of cellular mutations detected increases linearly with the number of packet-years.

However, the increase in mutations seems to level off and stop after 23 packet-years. The heaviest smokers apparently and implausibly did not have the highest mutation rates. The researchers proved that these people would have succeeded in suppressing the accumulation of mutations, because they would have very powerful systems for repairing DNA damage and detoxifying cigarette smoke. Soon, thanks to these discoveries, the group plans to develop new tests to measure a person’s ability to repair and detoxify their DNA.

Source: Nature Genetics

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