TORONTO--Cancer geneticists have found a new gene that could put some men at increased risk for prostate cancer, a disease that strikes one in six men in the general population. Data presented here last week at the annual meeting of the American Society of Human Genetics suggest that a relatively common variant of a gene involved in cell growth can raise cancer risk. The researchers also have a molecular explanation for why this variant may spur cancerous growth.
Researchers had already found a mutated version of the gene, Kruppel-like factor 6 (KLF6), in many prostate tumors; the change disrupts KLF6's normal role of inhibiting cell growth (Science, 21 December 2001, p. 2563). Now the same team at the Mount Sinai School of Medicine in New York City and collaborators have looked at whether some men are born with harmful KLF6 mutations. Lead investigator John Martignetti's group first identified a relatively common variant of KLF6 in families with a clear history of prostate cancer. They then screened for this variant, a single-base mutation, in blood samples from 3411 prostate patients and controls in registries at three major cancer centers, some with a family history of prostate cancer, some not. Compared to men lacking the variant, those with no family history of prostate cancer and at least one copy had a 42%increased risk for sporadic prostate cancer; men with a family history of the disease had a 61%increased risk.
The team also investigated how this KLF6 mutation changes the gene's function. They found that the protein encoded by KLF6 can come in three forms, and cells with the variant make more of the two truncated forms. Instead of entering the cell nucleus and suppressing cell growth, these shortened KLF6 proteins stay in the cell's cytoplasm, where they have the opposite effect. Tipping the balance of KLF6 proteins toward the short versions could therefore explain why the KLF6 variant raises cancer risk, Martignetti says.
Three other genes have been identified as raising a person's prostate cancer risk. Martignetti's team has made a convincing case to some that KLF6 is the fourth. "It's about as solid as it could be" for an initial study, says Sean Tavtigian of the International Agency for Research on Cancer in Lyon, France. And although the KLF6 variant alone may only slightly raise a man's risk, it could act in concert with other prostate cancer genes, Tavtigian notes. If researchers can pin down how those risks add up, clinicians could eventually use the information to advise patients who are especially susceptible to the cancer.