Scientists have discovered a new way for genetic mutations to lead to cancer--by rendering neighboring stretches of DNA more likely to be mutated. The serendipitous finding, reported in the September issue of Nature Genetics, could account for unexplained cases of colon cancer and help in the early detection of such cancers, especially in Ashkenazi Jews.
Inheritance seems to play a role in somewhere between 15% and 50% of colon cancers and the benign polyps that are often their precursors. Yet the colon cancer genes found so far have been linked to less than 5% of the total cases. A clue to what might explain the discrepancy came to light when a social visitor to Bert Vogelstein's lab at Johns Hopkins University School of Medicine mentioned that he had several colorectal polyps and a slight family history of colon cancer. As a courtesy, Vogelstein, whose lab had already uncovered a fistful of genes involved in the disease, offered to test the 39-year-old man for known mutations.
Vogelstein, Kenneth Kinzler, and other colleagues found a minor change in the APC gene, which normally holds cell growth in check and can cause colon cancers when mutated. At first glance the change appeared to be innocuous--a simple switch from a thymine (T) to an adenine (A). Such gene changes, called polymorphisms, are common. But curiously, the tumor-suppressor protein made by the gene began to pick up extra mutations in and around the region that contains the T-to-A switch. That apparently happened, Kinzler says, because the mutation creates a stretch of eight consecutive As, which can throw off the enzyme that transcribes the DNA and completely garble the resulting protein.
The team guessed that the string of A's could also confuse the enzyme that copies DNA when cells replicate, creating new--and more harmful--mutations. Indeed, all of the tumors from patients who carried this particular T-to-A mutation also had additional mutations that inactivate the APC gene. But blood cells from the same patients only had the T-to-A change--suggesting that the patients inherited the base change and developed the other mutations later, but only in the colon cells that became cancerous.
"This could be a landmark study of a novel mechanism," says molecular biologist Jeffrey Trent of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland. Trent and others says that the same mechanism might be at work in genes linked to other cancers, such as breast and prostate cancer, which have been found to contain similar "harmless" sequence variations.