Most people who develop lung cancer have a history of smoking. However, in up to a quarter of all cases, the patient has never lit up in their life.

A large new study on these so-called never smokers has now identified three unique subtypes of lung cancer that seem to arise with no apparent environmental trigger – such as smoke, asbestos, or air pollution.

"What we're seeing is that there are different subtypes of lung cancer in never smokers that have distinct molecular characteristics and evolutionary processes," explains epidemiologist Maria Teresa Landi from the United States' National Institute of Health.

"In the future we may be able to have different treatments based on these subtypes."

Today, smoking has caused a worldwide epidemic of lung cancer – with 2 million diagnoses occurring each year – yet it's still unknown how this disease arises in those who have never smoked at all.

The new research has now provided several clues as to how these non-smoker cancers originate.

When scientists sequenced the genomes of frozen tumor tissue, sampled from 232 never smokers diagnosed with non-small cell lung cancer (by far the more common of the two main types of lung cancer), they noticed several mutational signatures that were not apparent in normal lung tissue.

These genetic changes are slightly different to what occurs when tobacco smoke causes cancer, which suggests an alternative form of lung damage might be to blame, potentially something occurring in the person's body, like faulty DNA repair or oxidative stress.

Even those 62 never smokers who had been exposed to secondhand smoke showed similar signatures to other never smokers in their tumor tissue. This indicates their disease is a product of internal bodily changes and not environmental stressors, although the sample size in this case is relatively small.

"We need a larger sample size with detailed information on exposure to really study the impact of secondhand tobacco smoking on the development of lung cancer in never smokers," admits Landi.

The patients from this study were also mostly of European descent, which means future research will need to improve on the diversity of its participants.

That said, the authors have identified three novel subtypes of lung cancer in their cohort.

The first and most common subtype they have named piano (from the Italian music term for 'soft and quiet'), because it shows the fewest genomic mutations. This subtype of lung cancer is associated with progenitor cells, which help create new cells in the lung. It also grows slowly, which means it can be detected up to ten years in advance.

The second subtype is not so easily detected and grows really quickly. It has been named mezzo-forte because its genomic mutations are slightly 'louder' and stronger. This type of lung cancer appears to be linked to mutations in the growth factor receptor gene known as EGFR.

The final subtype of non-smoker lung cancer is called forte, the 'loudest' of the lot. It exhibits a mutation known as whole-genome doubling, which is also seen in lung cancers among smokers.

Even still, its genomic signatures do not strongly match tobacco smokers, even when the patients had experienced secondhand smoke.

"We're at the beginning of understanding how these tumors evolve," says Landi. "This analysis shows that there is heterogeneity, or diversity, in lung cancers in never smokers."

Knowing how natural lung cancers arise and how they differ from smoking-induced cancers is crucial if we want to treat them properly. Already, scientists are testing treatments that target mutations in the EGFR gene, and one day, these could prove effective for those with the mezzo-forte subtype of naturally occurring lung cancer.

The piano subtype, on the other hand, will probably be a bit harder to treat, as its genetic mutations seem to have multiple drivers, which makes them harder to target with drugs.

Even still, the authors note that if we can find a pharmaceutical that disrupts signals to the lungs' progenitor cells, it could help halt the growth of piano tumors.

The authors hope their investigations will continue to inspire drug research for lung cancers in the future, especially for those who have never puffed on a cigarette in their life.

The study was published in Nature Genetics.