News · Longevity & Aging
An inherited gene variant raised lung cancer risk more than smoking did, in 3.3 million people
Lung cancer in people who never smoked has long been hard to explain. A study of more than 3.3 million people links part of it to an inherited change in the EGFR gene, traced to a founder event in southern Appalachia.
- This genetic study of more than 3.3 million people links the inherited EGFR T790M variant to lung cancer.
- The added risk was larger than the risk from smoking, and several times larger in people who never smoked.
- Carriers had no raised risk of 17 other cancers that were checked.
- The variant is more common in the US, traced to a founder event in southern Appalachia 200 to 225 years ago.
- The variant is rare, and no screening program based on it exists yet.
One of the most uncomfortable facts in oncology is that people who never smoked still get lung cancer. Researchers have a category for it, never-smokers, and until now inherited risk has explained very little of it. A study published in Science, drawing on more than 3.3 million people, has identified one inherited change that does.
The variant is a single letter change in a gene called EGFR, known as T790M. In the people who carry it, the added lung cancer risk was larger than the risk that comes with smoking, and several times larger again in those who never smoked.
Why is lung cancer in never-smokers so hard to explain?
MedlinePlus calls smoking the most important risk factor for lung cancer, and says tobacco smoking causes about 9 out of 10 cases in men and about 8 out of 10 in women. But those figures leave a remainder. Studies of the genetics have mostly turned up variants that influence smoking behavior rather than cancer directly, which does not help explain cases in people who never took it up.
As the authors put it, inherited risk in familial and non-smoking-related lung cancers remains poorly understood. That gap matters clinically, because lung cancer screening programs are built around smoking history, and someone who never smoked will not qualify.
What is the EGFR T790M variant?
EGFR stands for epidermal growth factor receptor, a protein that sits on the surface of cells and tells them to grow. Changes in it are already familiar in cancer medicine: tumors often acquire EGFR mutations as they develop, and drugs that block the receptor are standard treatment for those cancers.
T790M is well known to oncologists for a different reason, as a change tumors pick up when they stop responding to those drugs. What this study is about is different. Here the variant is germline, meaning inherited and present in every cell of the body from birth.
How large was the risk, and how specific?
The researchers assembled data on more than 3.3 million individuals, a scale that matters because the variant is rare. Carriers had a significantly raised risk of lung cancer, and the size of that risk exceeds that conferred by smoking. In never-smokers it was several-fold higher still.
Two details make the finding more convincing. Carriers showed no increased risk for 17 other cancers that the team checked, which is what you would expect from something acting specifically on lung tissue rather than a general cancer predisposition. And there was no interaction with polygenic risk, the combined effect of many common variants, meaning this appears to act on its own rather than by amplifying other inherited risk.
Why does the variant cluster in the United States?
This is the part of the paper that reads like history rather than biology. The variant turned up more often in the US than in British- and Irish-descendant populations, and the researchers traced the difference to a founder event in southern Appalachia about 200 to 225 years ago.
A founder event happens when a small settling population happens to include someone carrying a rare variant. Their descendants inherit it at a much higher rate than the wider population, and the signature stays in the region’s genetics for centuries. In this case the authors report that the variant affects people of British, Irish and African descent in that region, a reminder that ancestry in the American South is mixed and a variant does not respect the categories used to describe it.
What can’t this EGFR study tell a carrier?
It cannot tell an individual carrier what will happen to them. The paper reports how much more often lung cancer occurred in carriers across millions of people; the abstract does not say what share of carriers go on to develop it, and the full paper sits behind a paywall that was not reviewed for this article.
Nor does it show that finding carriers early would save lives. That is the obvious next question, and answering it takes a screening study: offering scans to carriers, and checking whether cancers are caught earlier and fewer people die. The authors go only as far as saying recognition of high-risk carriers may inform targeted genetic testing and screening strategies.
What does this mean for families with unexplained lung cancer?
For most readers, nothing changes today. The variant is rare, no testing program exists for it, and the biggest lever on lung cancer risk is still tobacco.
Where it may matter is in families where lung cancer has appeared in people who never smoked, especially with Appalachian roots. That is worth raising with a doctor, who can weigh whether a referral for genetic advice makes sense. And the symptoms MedlinePlus lists, including chest pain or discomfort, a cough that does not go away or gets worse, and coughing up blood, deserve attention whether or not someone has ever smoked.
People also ask
What did the study find?
In more than 3.3 million individuals, the EGFR T790M germline variant was significantly associated with lung cancer risk, with no increased risk for 17 other cancers and no interaction with polygenic risk. The risk exceeds that conferred by smoking and is several-fold higher in never-smokers. Higher prevalence in the US than in British- and Irish-descendant populations reflects a Southern Appalachian founder event about 200 to 225 years ago.
What is EGFR?
A gene for a protein on the surface of cells that tells them to grow. Acquired changes in it are common in lung cancer, and drugs that block it are already used as treatment.
What does germline mean?
Inherited. A germline variant is present from birth in every cell, unlike a mutation a tumor picks up later.
What is a founder event?
When a small group of settlers happens to carry a rare variant, their descendants in that region carry it far more often than the wider population does.
Should I get tested for this variant?
There is no recommendation to do so. The variant is rare, and the authors describe their findings as information that may inform targeted testing and screening strategies, not as a reason for general testing.
Does this mean smoking is less dangerous than thought?
No. Most lung cancers are tobacco related. This is about a rare inherited variant whose effect, in the people who carry it, is larger than the effect of smoking. This is general information rather than medical advice.