15th September 2021

Genomic and evolutionary classification of lung cancer in never smokers

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Why do people who never smoke get lung cancer?

That fundamental question has proved to be a major challenge for researchers seeking to better understand how lung cancer develops.

In recent years, it has been observed that lung cancer in people who have never smoked seems to occur more frequently in women and at an earlier age than it does in those who smoke, or used to smoke.

Media reports often highlight cases where lung cancer has affected individuals who never smoked; people such as Ruth Strauss, wife of former England cricket captain, Andrew Strauss. She was just 46 when she died in 2018.

Michelle Gilliver, who shared her story with us to support our ‘Spot the Difference’ campaign, is another woman with no history of smoking who was diagnosed with lung cancer. There are many other examples.

It seems such a strange anomaly. Yet, as we so often stress in our own messaging, if you have lungs, you can get lung cancer.

We know that smoking tobacco products significantly increases your risk of developing the disease, but it is not the only cause – up to 28% of cases of lung cancer are not linked to smoking.

While environmental risk factors such as passive exposure to tobacco smoke, radon gas, air pollution and asbestos, or having had previous lung disease may explain some cases of lung cancer among those who have never smoked, we still do not know what causes most of these cases. 

Now a study, looking at the genetic make-up of people with no history of smoking who have been diagnosed with lung cancer, finds that most of their tumours were due to an accumulation of mutations caused by natural processes within their bodies. 

Genes make sure that the cells within our bodies grow and make copies (reproduce) in an orderly and controlled way; they are needed to keep the body healthy. Sometimes a change happens in the genes when a cell divides. This is a mutation – it means that a gene has been damaged or lost or copied too many times.

Mutations can happen by chance when a cell is dividing. Some mutations mean that the cell no longer understands its instructions and can start to grow out of control. This creates the mass or tumour we recognise as cancer.

The new study was carried out by an international team of scientists, led by researchers at the US National Cancer Institute (NCI), based in Rockville, Maryland, and published in the scientific journal Nature Genetics (Sept 6 2021).

What we see is that there are different subtypes of lung cancer in never-smokers that have different molecular properties and evolutionary processes.

Dr Maria Teresa Landi, National Cancer Institute, USA.

Unlocking the mystery

Insights from the study may help to unlock the mystery of how lung cancer occurs in people with no history of smoking and lead towards the development of more accurate clinical treatments.

The researchers used a technique called whole genome sequencing to identify and catalogue the genomic changes in tumour tissue.

In most cases, they matched tissue from 232 never-smokers, predominantly of European descent, who had been diagnosed with non-small cell lung cancer.

These tumours included 189 adenocarcinomas (the most common type of lung cancer), 36 carcinoids, and seven other tumours of various types. The patients had not yet undergone treatment for their lung cancer.

The researchers carefully examined the tumour genomes for mutation signatures – patterns associated with specific mutation processes, such as damage from natural activities in the body (for example, defective DNA repair) or exposure to chemicals that can cause cancer.  

Mutation signatures act as a tumour’s ‘archive’ of activities that led to the accumulation of mutations and provide clues as to what caused the cancer to develop.

A catalogue of known mutation signatures is now available, although some signatures have no known cause. In this study, the researchers discovered that most tumour genomes from never-smokers carried mutation signatures associated with damage from natural processes that take place inside the body (‘endogenous processes’). 

As expected, since the study was limited to never smoking, the researchers found no mutation signatures previously associated with direct exposure to tobacco smoking. They also did not find these signatures among the 62 patients who had been exposed to used tobacco smoke.

The genomic study also revealed three new subtypes of lung cancer in never-smokers, which were given musical names based on the level of “noise” (that is, the number of genomic changes) in the tumours:

  • – The dominant “piano” (or ‘’soft’’ in musical terms) subtype had the fewest mutations; it appeared to be associated with the activation of stem cells involved in the creation of new cells. This subtype of tumour grows slowly over many years and is difficult to treat because it can have many different driver mutations.
  • – The “mezzo-forte” (‘’medium-loud’’) subtype had specific chromosomal changes as well as mutations in the growth factor receptor gene EGFR, which usually changes in lung cancer and showed faster growth.
  • – The “forte’’ (‘’fast’’) subtype exhibited duplication of the entire genome, a change often seen in lung cancer in people who smoke. This subtype of tumour also grows rapidly.

Dr Landi, who is based at the Integrative Tumour Epidemiology Branch at the NCI’s Division of Cancer Epidemiology and Genetics, believes that the study marks the start of ways to distinguish between types that could potentially have different methods of prevention and treatment.

She said, “For example, the slow-growing piano subtype may provide clinicians with a window of opportunity to detect these tumours earlier when they are less difficult to treat. In contrast, the mezzo-forte and forte subtypes have few major driver mutations, suggesting that these tumours could be identified by a single biopsy and could benefit from targeted treatments.”

‘’We are in the beginning of understanding how these tumours develop. This analysis shows that there is diversity in lung cancer in never-smokers.”

A future direction for this research will be to study people with different ethnic backgrounds and geographical locations, and whose exposure history to risk factors for lung cancer is well described.

Dr Stephen J. Chanock, director of NCI’s Division of Cancer Epidemiology and Genetics, added: “We anticipate that this detective-style study of genomic tumour properties will unlock new pathways for multiple cancers.

If you would like to learn more about ways to quit smoking, we have practical advice and support here.