A large international study has identified the genetic pathways through which lung cancer occurs in people who have never smoked.
The research, which is published in Nature Genetics, showed that lung cancer that arises in non-smokers has a distinct genetic signature compared with smoking-related lung cancer and largely happens due to the accumulation of mutations occurring due to various natural processes.
“What we’re seeing is that there are different subtypes of lung cancer in never smokers that have distinct molecular characteristics and evolutionary processes,” said Maria Teresa Landi, a National Cancer Institute researcher and epidemiologist, who led the study in a press statement.
Lung cancer causes more deaths than any other cancer around the world and around 2 million people are diagnosed with this kind of cancer annually. While smoking is linked to 80-90% of cases, 10-20% of patients with lung cancer have never smoked. Despite this, most research to date has focused on smoking-related lung cancer and very little genomic data on lung cancer in never-smokers exists.
For this study, the research team used whole-genome sequencing to analyze tumor samples from 232 never smokers with non-small cell lung cancer. Most of the group were female (75.4%) and the average age at diagnosis was 65 years. The samples were taken from 189 adenocarcinomas, 36 carcinoids, and seven other different tumor types.
Landi and colleagues categorized the tumors into three main types. The most common were ‘quiet’ (piano) tumors that slowly develop over a number of years and have the smallest number of overall mutations, but can be difficult to treat because of a scarcity of driver mutations making the cancer origin hard to pinpoint and target. Among other factors, these tumors had UBA1 and KRAS mutations and stem cell-like properties, as well as high levels of variation between different tumors of this type.
The ‘medium intensity’ (mezzo-forte) tumors have mutations in the growth factor receptor gene EGFR, specific chromosomal changes and grew faster than the quiet tumors.
The final ‘loud’ (forte) type of tumors identified by the researchers seemed to be most similar to the kind of lung cancer seen in smokers. These tumors are the most aggressive of the three types, grow quickly and show whole-genome doubling.
“We’re at the beginning of understanding how these tumors evolve. This analysis shows that there is heterogeneity, or diversity, in lung cancers in never smokers,” commented Landi.
Although the quiet tumors develop more slowly, they tend to be harder to treat than the other two tumor types in this group when more advanced due to limited treatment targets. But the researchers believe their study could help to solve this problem and ideally diagnose these quiet cancers at an earlier stage.
“Targeting the KRAS and stem cell-associated signaling pathways, or regulating the stem cell microenvironment, are promising for this subtype,” they write.
