There is no need to say that smoking is the leading cause of lung cancer. We all know that by now. But still, there are 1.1 billion smokers worldwide. The World Health Organization estimates that 1.8 million deaths per year are associated to lung cancer, and the numbers keep raising.

The main reason why smoking leads to lung cancer is due to the great number of mutations that cells start to accumulate upon exposure to the carcinogens. However, there is still a long way to go in order to understand the initial consequences of smoking in healthy lung cells and how they evolve into squamous lung carcinoma.

Lung cancer present some of the highest mutation frequencies despite the fact that it is thought that only few oncogenic driver mutations are required to occur in a single cell to lead to cancer. Is there any role for all of these additional mutations? Within these lines, Yoshida et al. have studied the mutational profiles of 632 healthy lung cells obtained from whole-genome sequencing of different biopsied tissues from children, adults, non-smokers, current smokers and ex-smokers. As expected, aging is associated to the accumulation of mutations, 22 additional point mutations in a single cell per extra year of life and smoking is no surprise when it adds more than 5000 mutations. Former smokers still present more than 2000 mutations per cell. However, what was unexpected, is the huge difference in number of mutations in different cells from the same individual (around 10 fold in smokers). In fact, some mutational signatures are already present in non-smokers and are more abundant with age and more common in smokers.

According to Yoshida et al., although the risk of developing cancer in ex-smokers is significantly lower than current smokers, ex-smokers present similar smoking-associated mutation profiles in most of the lung cells, which increases their risk of lung cancer when compare to non-smokers. Luckily, this number seems to decrease depending on the length of time of smoking cessation, and in fact, eventually, 20-50% of the cells have a low mutation burden similar to the non-smoker´s profiles.

These data leaves us with a question: What is allowing ex-smokers to keep a small fraction of highly mutated cells that can proliferate if the exposure to carcinogens has been stopped? This proves that studying the underlying mechanisms of cancer is still a must.