Rare EGFR Gene Mutation Raises Lung Cancer Risk 62-Fold in Never-Smokers

Scientists have identified an inherited gene mutation that significantly increases the risk of lung cancer, even among people who have never smoked.

The mutation, known as EGFR T790M, affects the EGFR gene, which helps control cell growth, division and survival.

People who had never smoked and carried the EGFR T790M mutation were 62 times more likely to develop lung cancer than nonsmokers without the mutation, according to a study published Thursday, September 17, in Science.

How much does the EGFR T790M mutation increase lung cancer risk?

The study found that the mutation increased lung cancer risk independently of smoking status. By comparison, smokers who did not carry the mutation were four times more likely to develop lung cancer than nonsmokers without it.

Among smokers who carried EGFR T790M, the mutation was associated with an 11-fold increase in lung cancer risk compared with other smokers.

On average, people with the mutation were about 25 times more likely to develop lung cancer than people without it. This figure included both smokers and nonsmokers.

People with EGFR T790M also developed lung cancer about five years earlier, on average, than people without the mutation. The mutation was not associated with other types of cancer or with noncancerous lung disease.

“The prevalence of the T790M variant and its impact on lung cancer risk have been poorly understood until now,” said Chris Amos, a genetic epidemiologist at Baylor College of Medicine who was not involved in the study. He called the findings “a very important discovery.”

A rare inherited mutation with a strong effect

The study included more than 3 million people of European descent and found that approximately 1 in 15,850 people carried the EGFR T790M mutation.

Because the mutation is relatively rare, it is unlikely to account for a large proportion of all lung cancer cases. However, researchers say its strong effect on risk could be important for families in which lung cancer occurs among people who have never smoked.

Amos said genetic testing may be worth considering for people with a family history of lung cancer in nonsmokers or whose relatives are known to carry the mutation. Identifying EGFR T790M may also help guide treatment decisions in people who already have lung cancer.

How researchers found the EGFR mutation

The researchers combined genetic, geographic and historical data. They analyzed DNA and health information from more than 3.3 million people who used 23andMe home genetic testing kits and consented to having their data used for research.

Two large public genetic databases—the All of Us Research Program and the UK Biobank—contained only 19 and two people with the T790M mutation, respectively. By comparison, the 23andMe group included 641 people with the mutation, giving researchers enough data for a reliable statistical analysis.

Why the mutation is more common in parts of the Southeast

When researchers examined participants’ birthplaces, they found that the EGFR T790M mutation was much more common among people born in the Southeast, particularly Alabama, Mississippi and Tennessee.

In those three states, the variant was found in approximately 1 in 2,078 people who provided data to 23andMe.

Researchers used historical records to investigate how and when the mutation may have spread. They believe settlers from the British Isles brought it to the United States in the early 1700s. Families carrying the mutation later migrated to southern Appalachia, where relative isolation may have allowed it to be repeatedly inherited within the region.

Dr. Stephen Channock, director of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, was not involved in the study. He said the concentration of people with the mutation in the Southeast could help explain why lung cancer rates are higher in the region.

People in the region also smoke at higher rates than the U.S. average. Approximately 20% of adults in Appalachia report smoking, compared with 16% of adults in other parts of the United States. The genetic risk and smoking exposure may be interacting.

Could EGFR T790M change lung cancer screening?

People with a history of smoking may be advised to receive annual lung cancer screening with a low-dose CT scan, depending on their individual risk factors. However, researchers say an important unanswered question is when and how often people with the EGFR T790M mutation should be screened.

Because carriers developed lung cancer about five years earlier than people without the mutation, Amos said screening may need to begin at a younger age for people who carry it, regardless of whether they smoke.

A clinical trial is currently evaluating CT-based lung cancer screening for people with the mutation. The trial will also examine whether lung cancer risk increases with age in this population.

What researchers hope to learn next

Future studies will need to clarify why EGFR T790M increases lung cancer risk and whether environmental exposures interact with the mutation. Researchers identified particulate matter pollution in the atmosphere as one important factor to investigate.

Scientists may also search for additional inherited mutations that contribute to lung cancer risk. Channock said more rare variants may eventually be identified, while Amos noted that other EGFR variants could increase risk but may be even rarer than the mutations studied in this research.

Finding these variants could help people who carry them proactively manage their risk of developing lung cancer through personalized medical advice, screening and treatment planning.