People who inherit a rare change in the EGFR gene may be much more likely to develop lung cancer. Their risk is about 25 times higher than that of people without the mutation. Among people who have never smoked, the risk is nearly 62 times higher.

Researchers say this may be one of the strongest known inherited risk factors for cancer.

“Precision medicine has usually used the genetic features of a tumor to guide treatment,” said study co-leader Jaclyn LoPiccolo, MD, PhD, of the Dana-Farber Cancer Institute. “Our results suggest another use for genetics: identifying people who are at high risk before cancer develops, so the disease can be found earlier.”

Most lung cancer cases are linked to smoking. However, lung cancer is also becoming more common among people who have never smoked, and scientists still do not fully understand the inherited factors involved.

The mutation studied is called EGFR T790M. Scientists first identified it in 2005 in a European family in which several relatives had lung adenocarcinoma, a common type of lung cancer. Other families with the same mutation have since been reported, but the mutation is so rare that its overall frequency and cancer risk were not clear.

To learn more, researchers analyzed genetic information from:

• 9,799 people with lung cancer
• 3,362,732 people without a history of lung cancer

All participants were of European ancestry and had used the genetic-testing company 23andMe.

The researchers found that about one in 15,850 people carried the EGFR T790M mutation. Overall, carriers had a 25.2-times higher risk of lung cancer.

For comparison, smoking was linked to a 3.8-times higher risk of lung cancer in this study. The inherited BRCA1 and BRCA2 mutations, which are associated with breast cancer, have been linked to risks that are about 7.6 and 5.2 times higher, respectively.

The effect of EGFR T790M differed depending on whether a person smoked:

• People who had never smoked: about 7 times higher risk
• People who smoked: about 6 times higher risk

The researchers said this does not mean smoking is protective for mutation carriers. Smoking remains a major cause of lung cancer, and people with the mutation should avoid smoking.

The larger relative risk among nonsmokers may partly be explained by their lower usual risk of lung cancer. When the normal risk is low, a powerful inherited risk factor can make the difference appear especially large.

The mutation did not appear to increase the risk of 17 other cancers examined, including breast, colorectal, ovarian, prostate, and blood cancers. It also was not linked to several noncancerous lung diseases, such as chronic bronchitis, COPD, or interstitial lung disease.

This narrow effect makes sense because the EGFR gene plays an important role in the cells lining the lungs.

The researchers also found geographic differences among the 641 people who carried the mutation. It was more common in the United States than among people with British or Irish ancestry. It was especially frequent in the Southern Appalachian region, where about one in 2,078 people carried it.

The researchers said these findings could eventually help identify people who may benefit from earlier or more frequent lung cancer screening, especially those who have never smoked.

They now plan to study whether the risk changes with age, how likely carriers are to develop lung cancer during their lifetime, and why some carriers develop cancer while others do not.

If the mutation is found during testing of a lung tumor, additional germline testing is needed to determine whether it was inherited or developed only in the tumor. The researchers hope their findings will eventually help guide CT screening and detect lung cancer at an earlier, more treatable stage.