Right now, in your body, lurk thousands of cells with DNA mistakes that could cause cancer. Yet only in rare instances do these DNA mistakes, called genetic mutations, lead to a full-blown cancer. Why? The standard explanation is that it takes a certain number of genetic “hits” to a cell’s DNA to push a cell over the edge. But there are well-known cases in which the same set of mutations clearly causes cancer in one context, but not in another. A good example is a mole. The cells making up a mole are genetically abnormal. Quite often, they contain a mutated DNA version of the BRAF gene that, when found in cells located outside of a mole, will often lead to melanoma. But the vast majority of moles will never turn cancerous. It’s a conundrum that has scientists looking to cellular context for clues to explain the difference.
The scientists say their results offer an important new perspective on cancer formation, one that contrasts with conventional wisdom. “The standard idea that has been around for decades is that you basically need two types of DNA mutations to get cancer: an activated oncogene and a disabled tumor suppressor gene,” Dr. White says. “Once you clear those two hurdles, cancer will form. Now we have this entirely other thing—oncogenic competence—which adds a third layer to the mix.” Dr. Baggiolini, a lead author on the study and a postdoctoral fellow in the Studer lab, likens the situation to starting a fire. “The DNA mutations are like a lit match: If you have the wrong wood or if the wood is wet, you might get a bit of flickering but no fire. But if you have the right wood, and maybe some kindling, the whole thing burns up.” In this example, ATAD2 is the kindling. Developing a drug to remove this kindling would be another way to treat the cancer besides targeting the DNA mutations.