• Researchers sequenced the genetic codes of non-small cell lung cancer (NSCLC) tumors in 232 people who had never smoked and had not undergone treatment.
• Results indicated that there are three distinct subtypes of NSCLC based on the type and number of mutations found in the tumors.
• Researchers hope the findings will lead to the discovery of new lung cancer treatments.

DNA mutations that have accumulated over time are a cause of lung cancer in people who have never smoked, according to a study from the National Cancer Institute, part of the National Institutes of Health (NIH). A report released on Sept. 6 from the NIH describes three distinct subtypes of lung cancer in people who were never smokers. Researchers hope these findings can lead to advances in lung cancer treatment.

The study looked at tumor tissue from 232 people, predominantly of European descent, with non-small cell lung cancer who had not yet been treated. Researchers performed whole-genome (genetic code) sequencing on DNA from the tumors and compared it to normal tissue from those same participants to look for common mutations, known as mutational signatures. Of the 232 tumor samples, 189 were adenocarcinomas (which are the most common type), 36 were carcinoids, and seven were other subtypes.

Lung cancer is caused mainly by exposure to cancer-causing agents known as carcinogens. The most common carcinogen is tobacco smoke; secondhand exposure to this smoke can also cause lung cancer. Other environmental risk factors can include breathing in radon, asbestos, and air pollution, all of which may cause lung cancer in some who have never smoked. However, scientists are still uncertain what causes most cases of lung cancer that aren't related to smoking.

After sequencing the tumor DNA, the researchers looked for patterns of mutations in certain genes that could be linked to cancer. For example, they looked at genes involved in DNA repair or oxidative stress, both of which are turned on after exposure to carcinogens. By observing tumors gaining new mutations, researchers can better understand what can cause a particular cancer to develop in the first place.

The whole-genome sequencing data helped the researchers identify three new distinct subtypes of lung cancer in people who have never smoked. They are hopeful that this information can lead to new discoveries in treatment. “In the future we may be able to have different treatments based on these subtypes,” stated Dr. Maria Teresa Landi, senior investigator and senior advisor for genomic epidemiology at NCI.

Researchers gave the three subtypes music-themed names, based on the level of “noise” they had; that is, the range in the number of mutations found in the DNA. The three subtypes were dubbed:

• Piano — The quietest (with the fewest mutations)
• Mezzo-forte — Medium loud
• Forte — The loudest (with the most mutations)

“Piano” tumors were found to grow from specialized progenitor cells, which are responsible for helping make new cells. These tumors grow slowly over the span of many years and can be difficult to treat by the time they are found.

“Mezzo-forte” tumors were found to have mutations in the epidermal growth factor receptor (or EGFR) gene, which is commonly mutated in lung cancers. These tumors tended to grow faster than the piano tumors.

Finally, “forte” tumors also grow quickly, and they often contain sets of divided DNA — that is, four strands of DNA instead of two. This is known as “whole-genome doubling” and is common in lung cancers that develop in smokers.