When you hear about lung cancer, the leading cause of cancer deaths, the first cause-connection that comes to mind is “smoking.” And that’s a correct link…to a certain extent. Although smoking is the biggest risk factor for lung cancer, about 10 percent to 20 percent of individuals with lung cancer have never smoked tobacco. Researchers refer to these people as “never smokers.” Lung cancer in never smokers is more common in women and tends to occur at an earlier age than the average diagnosis (which is 65 and older).

Why never smokers get lung cancer for the most part is a mystery. Now, a team of international investigators has begun to crack the genetic code of never smokers to unravel why some of these individuals develop this deadly disease.

Gene Mutations Tell a DNA Story

Led by the National Cancer Institute, part of the National Institutes of Health, the research team used whole-gene sequencing on tumor tissue from 232 never smokers with lung cancer and compared their genes to tissues from healthy never smokers. Whole-genome sequencing means identifying all the DNA in a person’s cells. The researchers were looking for patterns of gene mutations called mutational signatures.

A mutational signature tells researchers how a tumor starts to grow. From prior research,

mutational signatures have been cataloged for many types of cancer. There are mutational signatures that are caused by specific types of carcinogens, the substance that causes cancer. Cancer mutations may also start from the natural process of cell damage and repair not caused by a carcinogen, which also has a mutational signature. The results of the study are published in the journal Nature Genetics.

Three Cancer Subtypes Can Target Treatment

Based on the mutational signatures they found, the investigators created three subtypes for lung cancer in never smokers. They gave the subtypes musical names based on the levels of genetic changes…

  • Piano subtype is the most common. It has the fewest mutations, and it grows slowly over years.
  • Mezzo-forte subtype has more mutations, grows more quickly than piano type and has a known lung cancer mutation gene called EGFR.
  • Forte subtype grows most quickly, and has a genomic signature called whole-genome doubling, which is also seen in smokers. Whole-genome doubling means that all the chromosomes in cancer cells have been doubled, giving cancer cells a high survival rate.

Knowing the subtype helps doctors determine how a cancer will behave and may lead to better treatments, called targeted therapies. Many targeted therapies are already being used. For example, the EGFR mutation helps cancer tumors increase their blood supply, and drugs that target this gene specifically curb this activity.

As researchers learn more about the genes of these cancers, strategies for prevention and treatment may follow. The research team would like to do genomic testing on more patients and focus on possible risk factors such as race and geographic location.

For more information on lung cancer in nonsmokers: Visit the Centers for Disease Control and Prevention website at CDC.gov/cancer/lung/nonsmokers.

Source: Study titled “Genomic and Evolutionary Classification of Lung Cancer in Never Smokers,” by researchers at the National Cancer Institute, Bethesda, Maryland, et al., published in Nature Genetics.

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