Rare Gene Variant Raises Never-Smokers' Lung Cancer Odds 62-Fold, Study Finds in Science

BOSTON — A rare inherited change in the EGFR gene was tied to a sharp rise in lung cancer risk, including among people who have never smoked, according to a study in the journal Science.

Researchers at Dana-Farber Cancer Institute and 23andMe Research Institute analyzed data from more than 3.3 million people. They reported that the EGFR T790M variant raised lung cancer risk about 25-fold compared with people who did not carry it. Among never-smokers, carriers had about 62 times the odds of lung cancer compared with never-smokers without the mutation.

The variant did not show a similar increase across 17 other cancers in the same analysis.

Most U.S. carriers were traced to a shared ancestry linked to British and Irish settlers in Southern Appalachia about 200 to 225 years ago, the team said. Nationwide, the mutation remains uncommon — roughly one in 15,000 to 16,000 people. In some parts of Southern Appalachia, researchers estimated as many as one in 2,000 people may carry it.

Jaclyn LoPiccolo, an attending physician and lung cancer researcher at Dana-Farber and a co-author, said in a statement released with the paper: "Today, lung cancer screening is driven almost entirely by smoking history. Our findings raise the possibility that, in the future, screening could also be dictated by inherited genetic risk. If further studies confirm the benefit, people with EGFR T790M could be identified through genetic testing and offered personalized CT screening to identify lung cancers when they are at their most curable stage."

She added: "We found that the vast majority of carriers inherited the mutation from the same ancestral lineage. We could trace that lineage to British and Irish settlers in the United States and show that the mutation became enriched after a founder event and genetic bottleneck in Southern Appalachia about 200 years ago. It's a fascinating example of how human migration and genealogy can shape disease risk, generations later."

Alexander Gusev, a quantitative geneticist at Dana-Farber, said: "To my knowledge, it's one of the strongest, if not the strongest, cancer risk-increasing mutations that has ever been found."

On smoking he said: "Smoking is bad for lung cancer. This mutation is bad for lung cancer. When you do both, your risk is the sum of those two risks. So, you definitely don't want to smoke."

U.S. screening guidelines still center on age and pack-years of cigarettes. Never-smokers who develop lung cancer often present later. EGFR mutations are already familiar to oncologists as targets in tumor DNA. An inherited T790M change is different: it is present in every cell from birth, not only in a tumor that has evolved resistance to certain drugs.

The authors suggested that people with a strong family history of lung cancer, multiple lung nodules or tumors, or family roots in parts of the southeastern United States consider speaking with a genetic counselor about testing or CT screening. That is a clinical conversation, not a population mandate.

The study has limits the authors and the Fox News account both flagged. Because the mutation is rare, researchers found relatively few carriers even in a multimillion-person dataset, so the exact size of the risk increase is uncertain. Much of the sample came from 23andMe research participants, who may not match the broader U.S. population. Risk estimates may not apply equally outside the regions where the founder effect is strongest.

The work shows association, not proof that genetic testing cuts deaths. No trial in this report showed that offering CT scans to T790M carriers improves survival. Funding included the National Institutes of Health and the American Cancer Society.

Lung cancer remains a leading cause of cancer death in the United States. Smoking still drives most cases. The new finding does not invert that fact. It adds a small, geographically clustered group whose risk is high even without cigarettes — and higher still if they smoke.

For clinicians, the practical next step is pedigree and geography: unexplained family clusters of lung cancer, especially among never-smokers with Appalachian or British-Irish roots, may justify counseling. For everyone else, the mutation is too rare to turn into a mass screening add-on without more outcome data.

Gusev's arithmetic is the line that travels. The gene is bad. Smoking is bad. Together they add. Quitting does not erase an inherited allele. It still removes one of the two stacked risks.