New research links a rare variant of the BRCA2 gene to an increased risk of squamous cell lung cancer among smokers.

Smokers generally have about a 13% lifetime risk of lung cancer. New research suggests overall risk nearly doubles to about 25% among smokers who harbor a particular BRCA2 mutation.

The findings, published in June in Nature Genetics, found a previously unknown link between lung cancer and a specific BRCA2 defect called BRCA2 c.9976T. The defect occurs in slightly more than 2% of smokers, the authors note.

According to data from the Centers for Disease Control and Prevention, 42 million U.S. adults smoke. That means as many as 840,000 adult smokers may harbor this genetic mutation and have a one in four chance of developing lung cancer.

Literature dating back to the 1970s implicates inherited genetic factors in the development of lung cancer, says Christopher Amos, PhD, the study's senior author and director of the Center for Genomic Medicine at Dartmouth's Geisel School of Medicine in Hanover, NH. “Now we've identified a subset of people who are particularly susceptible to the effects of tobacco smoking due to genetics.”

Researchers discovered the link after comparing the DNA of 11,348 lung cancer patients of European descent with 15,861 people without lung cancer. The connection between lung cancer and mutant BRCA2—a well-known risk factor for breast, ovarian, and aggressive prostate cancers—was especially strong in patients with squamous cell carcinoma.

In contrast, scientists found that a rarer defect in the tumor suppressor gene CHEK2 appears to protect smokers from lung cancer. Researchers also identified a variant in the TP63 gene that slightly increases the risk for lung adenocarcinoma, a link previously reported only in Asians.

The results are currently limited to people with European ancestry. “Further research that identifies the mechanism by which the variants influence lung cancer risk would allow the findings to generalize to other populations,” says Amos.

The authors suggest squamous cell lung cancer patients with a BRCA2 mutation may benefit from PARP inhibitors, a class of drugs designed for cancers with mutations in the BRCA1 or BRCA2 gene. Clinical trials are already under way testing PARP inhibitors in advanced squamous cell lung cancer.

These new genetic insights may also allow clinicians to eventually target lung cancer screening to smokers at highest risk. “Going forward, we will get to a point where a tailored assessment of genetic factors along with biomarkers can help prioritize who should be screened,” says Amos.

Although Amos does not currently recommend genetic testing for smokers, those who are tested for other reasons should be told their BRCA2 gene variant status and informed about lung cancer screening. “Even with these genetic links, the best thing a person can do to lower their lung cancer risk is not to smoke,” he says.