About 25 percent of smokers who carry a defect in the BRCA2 gene will develop lung cancer at some point in their lifetime, according to data from a large-scale, international study published in Nature Genetics.

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The research, led by Richard S. Houlston, MD, PhD, Professor of Molecular and Population Genetics at the Institute of Cancer Research (ICR), showed a previously unknown link between lung cancer and a particular BRCA2 defect-BRCA2 c.9976T-occurring in around two percent of people.

The defect increases the risk of developing lung cancer by about 1.8 times, the team reported.

As explained in a news release, smokers as a group have a lifetime risk of developing lung cancer of about 13 percent (16% in men and 9.5% in women), but the study suggests that around one in four smokers with the BRCA2 defect will develop lung cancer

The researchers compared the DNA of 11,348 Europeans with lung cancer and 15,861 without the disease, looking for differences at specific points in their DNA. The research was mainly funded by the U.S. National Institutes of Health, with additional support from Cancer Research UK.

The link between lung cancer and defective BRCA2 was particularly strong in patients with the most common lung cancer subtype-i.e., squamous-cell lung cancer. The researchers also found an association between squamous-cell lung cancer and a defect in a second gene, CHEK2, which normally prevents cells from dividing when they have suffered damage to their DNA.

The results suggest that in the future, patients with squamous cell lung cancer could benefit from drugs specifically designed to be effective in cancers with BRCA mutations-for example, PARP inhibitors, which have been effective in breast and ovarian cancer patients with BRCA mutations.

"Our study showed that mutations to two genes, BRCA2 and CHEK2, have a very large effect on lung cancer risk in the context of smoking," Houlston said. "Mutated BRCA2 in particular seems to increase risk by around 1.8 times. Smokers in general have a nearly 15 percent chance of developing lung cancer-far higher than in non-smokers. Our results show that some smokers with BRCA2 mutations are at an enormous risk of lung cancer-somewhere in the region of 25 percent over their lifetime.

"Lung cancer claims more than a million lives a year worldwide. We know that the single biggest thing we can do to reduce death rates is to persuade people not to smoke, and our new findings make plain that this is even more critical in people with an underlying genetic risk."

RICHARD S. HOULSTON, MD, PhD. RICHARD S. HOULSTON, MD, PhD: "We know that the single biggest thing we can do to reduce death rates is to persuade people not to smoke, and our new findings make plain that this is even more critical in people with an underlying genetic risk."