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Why do people who have never smoked get lung cancer?

For the first time, researchers have described three molecular sub-types of lung cancer in patients who had never smoked, based on the number of genomic changes in their tumours.

Lung cancer is the leading cause of cancer-related deaths worldwide – over 2 million people worldwide are diagnosed with the disease each year. It is now well recognised that the risk of lung cancer increases with the number of cigarettes an individual has smoked. But what is less well known, is the fact that up to 20% of patients who develop lung cancer have never smoked at all.

“But I never smoked”

Lung cancer in never-smokers is much more likely to occur in women. It also typically arises at an earlier age than compared to those who smoke. Historically, scientists have debated about whether the absolute number of non-smoker patients is increasing. But now, evidence is emerging that clearly shows that the proportion of people with lung cancer who have never smoked is growing.

A previous US study of over 12,000 lung cancer patients found that, between 1990 and 1995, just 8% were non-smokers. But they reported that from 2011 and 2013 the proportion had risen to 14.9%. An even larger increase was found in the UK, with 13% of lung cancer patients having never smoked in 2008 growing to 28% in 2014.

Andrew Kaufman, a surgeon at Mount Sinai Hospital in New York, has said: “Since the early 2000s, we have seen what I think is truly an epidemiological shift in lung cancer. If lung cancer in never-smokers were a separate entity, it would be in the top 10 cancers in the U.S for both incidence and mortality”.

Environmental risk factors are thought to explain some cases of lung cancer among never smokers, such as exposure to second-hand smoke, air pollution or a history of other lung diseases. But the genomic landscape of these diseases remains poorly characterised, and understandably, there is now a growing pressure to understand lung cancer in never-smokers in more detail. 

Molecular subtypes of lung cancer in never-smokers

Recently, an international team led by researchers at the National Cancer Institute conducted a genomic analysis of lung cancer in people with no history of smoking. Whole genome sequencing was performed to search for mutational signatures in the tumour tissue of over 230 lung cancer patients who were never-smokers and had not yet started treatment.

Effectively, mutational signatures act like an archive of a tumour’s activities and provides clues as to what causes the cancer to develop. During this study, the researchers discovered that the majority of lung tumours in never-smokers contained mutational signatures associated with natural processes that occur within the body, not as a result of environmental factors.

Subsequently, for the first time, three molecular sub-types of lung cancer in patients who had never smoked were described using musical terms, based on the number of genomic changes, or ‘noise’, in the tumours:

  • ‘Piano’: This was labelled the dominant sub-type in non-smokers, but rare in lung cancers of smokers. It featured somatic UBA1 mutations, germline AR variants, low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth. In fact, it was discovered that the founder cells of ‘piano’ appeared around a decade before diagnosis.
  • ‘Mezzo-forte’: This sub-type was found to have specific chromosomal changes and EGFR mutations, both of which are relatively common in lung cancer. The ‘mezzo-forte’ sub-type also exhibited faster tumour growth than ‘piano’.
  • ‘Forte’: This sub-type showed whole genome doubling, which is often seen in the lung cancer of smokers. The ‘forte’ sub-type, like ‘mezzo-forte’, showed rapid tumour growth.

Unlocking the mystery of non-smoker lung cancer

The findings from this new study will no doubt create avenues for the personalised treatment of lung cancer in never-smokers. The more scientists can understand about the development of lung tumours in patients who have no history of smoking, the increased likelihood of developing novel and more precise clinical treatments for the disease.

Doctor Maria Landi, a leader in the study from the National Cancer Institute, explained: “What we’re seeing is that there are different subtypes of lung cancer in never smokers that have distinct molecular characteristics and evolutionary processes. In the future, we may be able to have different treatments based on these subtypes.”

For example, recognising the slow growing ‘piano’ sub-type could provide clinicians with optimal opportunities for early detection when the tumours are less difficult to treat. Equally, ‘mezzo-forte’ and ‘forte’ sub-types, which only have a few major driver mutations, could be identified by a single biopsy and may benefit from targeted treatments.

Although no mutational signatures were found in those patients who had been exposed to second-hand smoke, the sample size in this study was small. This highlights the need for future research to focus on large cohorts of patients from different ethnic backgrounds and varied geographical locations. Intelligence gathered from these studies will be extremely useful for understanding how lung tumours in never-smokers differs from that of smokers and for reviewing whether the current cancer screening guidelines need revision.

Image credit: HealthCentral

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Cancer Research / Genomics / Lung Cancer