The results also offer a different take on the two-hit model in carcinogenesis, Amon said. Being remarkably unstable, cancer cells can delete gene copies at every turn of the corner. If the loss of a single tumor suppressor copy provides no survival advantage for the tumor, then the tumor has no incentive to retain the cell with that deletion. But if the loss of that copy boosts proliferation, then the probability of a second hit later is greatly increased. "So haploinsufficiency is a way for the cancer cell to dramatically accelerate the acquisition of growth beneficial mutations," Amon said.
In other words, all it takes is a 50 percent reduction in gene activity for a cancer cell to grow. "That tells us it's a lot easier to get cancer than we might have hoped," Amon said.
According to Elledge, the number of hemizygotic deletions averages roughly six per tumor, with some tumorsbreast and pancreatic, for instanceaveraging up to ten. Each deletion involves 25 to 40 genes, many of them STOP genes, but also a few GO genes (growth enhancers and oncogenes) that enhance proliferation. That the STOP genes substantially outnumber their GO counterparts is important, Elledge explained, because it means cancer cells can tilt scales toward proliferation without also compromising it at the same time.
"The data reveal a lot of haploinsufficient players that have small effects individually, but large effects in combination," Elledge said. "Unfortunately, it's not easy to see how to take advantage of that chemotherapeutically."
What's important about the results, he emphasized, is that they open up new views on how tumors evolve. Mor
|Contact: David Cameron|
Harvard Medical School