An inherited EGFR variant carried 62-fold lung cancer odds among never-smokers

A study published Thursday, Sept. 17, in the journal Science identified an inherited mutation in the EGFR gene, called EGFR T790M, that greatly increases lung cancer risk, including in people who have never smoked.

People who had never smoked and who carried EGFR T790M were 62 times more likely to develop lung cancer than nonsmokers without the mutation.

On average, people with the mutation had about 25 times the odds of developing lung cancer compared with people without it, a figure that includes both smokers and nonsmokers.

Experts said the variant likely only plays a role in a small portion of never-smoker lung cancer cases, STAT reported.

The research provides further evidence that never-smoker lung tumors can be tied to distinct risk factors, which may require thinking differently about screening programs and treatment strategies, STAT reported.

People who smoked but did not carry the mutation were four times likelier to develop lung cancer than nonsmokers, so the mutation alone carried a higher risk than smoking.

Among study participants who smoked and carried the mutation, T790M increased cancer risk 11-fold compared with other smokers.

The study included over 3 million people of European ancestry, and the mutation showed up in 1 out of every 15,850 people.

All of Us and the UK Biobank, two of the largest public genetic databases to date, contained just 19 and two individuals with T790M respectively, while the 23andMe cohort included 641 carriers, enough to run reliable statistical analyses.

"The prevalence of the T790M variant and its impact on lung cancer risk has previously been poorly understood."

Amos called the result a "very important finding".

T790M was not linked to any other type of cancer or to noncancerous lung conditions.

The mutation was much more common among participants born in the Southeast, especially Alabama, Mississippi and Tennessee, where it showed up in 1 out of every 2,078 people who contributed data to 23andMe.

Researchers think settlers from the British Isles first brought the mutation to the U.S. in the early 1700s, and that families with it later moved to southern Appalachia, where relative isolation meant the variant was passed down repeatedly and became unusually common.

Certain populations with a history of smoking are recommended to get screened annually for lung cancer using low-dose CT scans.

A key question, Chanock said, is when and how often people with the T790M mutation should be screened.

People with T790M developed lung cancer about five years earlier than people without the mutation, on average.

That finding highlights the "need to begin screen[ing] at an earlier age and irrespective of smoking status", Amos said.

A clinical trial is now under way to evaluate CT-based lung cancer screening in people with the mutation.

Among people diagnosed with lung cancer, the prevalence of nonsmokers has been increasing, according to STAT.

The 641 carriers reported within the 3.3 million consented cohort imply a frequency of about 1 in 5,150.

The cohort-wide implied frequency is about three times the reported carrier rate of 1 in 15,850.

The relative risk for never-smoking carriers is about 15.5 times the relative risk associated with smoking without the variant.

Carriers who smoked had roughly 44 times the odds of a nonsmoker without the variant.

A purely multiplicative combination of the two risk factors would have predicted about 248 times the baseline odds for a carrier who smoked.

The 23andMe cohort held about 30 times as many carriers as All of Us and the UK Biobank combined.

The carrier rate in Alabama, Mississippi and Tennessee is about 7.6 times the overall reported rate.

At the reported frequency, finding one carrier by untargeted genotyping means testing about 15,850 people.

The concentration of people with T790M in the Southeast may help explain why the region experiences elevated lung cancer rates, Chanock said.

Approximately 20% of adults in Appalachia report smoking, compared with 16% of adults elsewhere in the U.S., so it is possible the two factors interact.