BRCA2, the defective gene linked to breast cancer and ovarian cancer, has now found to play a role in people who develop lung cancer.
One in four smokers who carry it will develop lung cancer, a large-scale study has shown. In fact, scientists found that a specific flaw in the gene almost doubles the overall risk of lung cancer.
A quarter of smokers, who generally have a 13% life-time risk of lung cancer, were predicted to develop the disease if they had the mutation.
Of the 10 million adults who smoke in the UK, up to 200,000 are thought to fall into this category.
Study leader Professor Richard Houlston, from the Institute of Cancer Research in London, said: "Our results show that some smokers with BRCA2 mutations are at an enormous risk of lung cancer - somewhere in the region of 25% over their lifetime.
"Lung cancer claims more than a million lives a year worldwide and is by far the biggest cancer killer in the UK. 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."
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The scientists scoured the DNA of more than 17,000 Europeans with and without lung cancer looking for any differences linked to the disease.
They spotted a specific alteration in the genetic code of BRCA2 known as c.9976T that was strongly associated with lung cancer.
It was especially prevalent among patients with the most common form of the disease, known as squamous cell lung cancer.
A weaker link between this lung cancer sub-type and another defective gene, CHEK2, was also identified.
The results, published in the journal Nature Genetics, open up the possibility of personalised treatment for lung cancer patients with BRCA2 mutations.
A family of drugs called PARP inhibitors has been shown to benefit breast and ovarian cancer patients with defective versions of the gene. However, it is not known if they would be equally effective against lung cancer.
Professor Paul Workman, deputy chief executive of the Institute of Cancer Research, said: "These findings indicate that around a quarter of smokers with a specific defect in their BRCA2 gene will develop lung cancer - a disease which is almost invariably fatal.
"All smokers are taking a considerable risk with their health, regardless of their genetic profile, but the odds are stacked even more heavily against those with this genetic defect who smoke."
BRCA2 is a tumour-suppressor gene involved in the repair of damaged DNA. When it stops working properly, cancer has a greater chance of taking hold.
Although mostly associated with women's cancers, defective BRCA2 can raise a man's lifetime risk of prostate cancer by up to 25%.