Chromosomal deletions in DNA often involve just one of two genecopies inherited from either parent. But scientists haven't knownhow a deletion in one gene from one parent, called a "hemizygous"deletion, can contribute to cancer . A research team led by Stephen Elledge, a professor in theDepartment of Genetics at Harvard Medical School, and hispost-doctoral fellow Nicole Solimini, has now provided an answer.The most common hemizygous deletions in cancer, their researchshows, involve a variety of tumor suppressing genes called STOPgenes (suppressors of tumorigenesis and proliferation) that scatterrandomly throughout the genome, but that sometimes cluster in thesame place on a chromosome. And these clusters, said Elledge, whois also a professor of medicine at Brigham and Women's Hospital,tend to be deleted as a group. "Eliminating the cluster gives abigger bang for the deletion buck," he said. |
This finding is especially interesting in light of the two-hitmodel of cancer formation, which holds that both copies of arecessive gene need to be inactivated to trigger a biologicaleffect. Thus the loss of a single tumor suppressor copy should havelittle or no influence on tumor cell proliferation because theremaining copy located on the other chromosome is there to pick upthe slack. Elledge's research points to a different hypothesis, namely thatSTOP genes in a hemizygous deletion aren't recessive but areinstead haploinsufficient, meaning that they depend on two copiesto function normally. "If a tumor suppressor is haploinsufficient,then a single gene copy lacks the potency needed to fully restraintumorigenesis," Elledge explained, who is also a Howard HughesMedical Institute Investigator. "So by removing clusters ofhaploinsufficient genes all at once, the cancer cell immediatelypropels its growth forward without having to wait for the othercopies to also be lost." Angelika Amon, a professor of biology at the Massachusetts ofTechnology, said she's surprised by the findings.
"We've known froma lot of human syndromes that haploinsufficiency is widespread inthe development of complex multicellular organisms," she said. "Butthese data show it's also critical for individual cells and cellproliferation." The results also offer a different take on the two-hit model incarcinogenesis, Amon said. Being remarkably unstable, cancer cellscan delete gene copies at every turn of the corner. If the loss ofa single tumor suppressor copy provides no survival advantage forthe tumor, then the tumor has no incentive to retain the cell withthat 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 dramaticallyaccelerate the acquisition of growth beneficial mutations," Amonsaid. In other words, all it takes is a 50 percent reduction in geneactivity for a cancer cell to grow. "That tells us it's a loteasier to get cancer than we might have hoped," Amon said. According to Elledge, the number of hemizygotic deletions averagesroughly six per tumor, with some tumors - breast and pancreatic,for instance - averaging up to ten.
Each deletion involves 25 to 40genes, many of them STOP genes, but also a few GO genes (growthenhancers and oncogenes) that enhance proliferation. That the STOPgenes substantially outnumber their GO counterparts is important,Elledge explained, because it means cancer cells can tilt scalestoward proliferation without also compromising it at the same time. "The data reveal a lot of haploinsufficient players that have smalleffects individually, but large effects in combination," Elledgesaid. "Unfortunately, it's not easy to see how to take advantage ofthat chemotherapeutically." What's important about the results, he emphasized, is that theyopen up new views on how tumors evolve. Moreso, they underscore theimportance of proliferation as a fundamental feature of tumorgrowth, he added.
The challenge now, Elledge said, will be to find out which of thegenes in a recurring deletion are haploinsufficient. "At themoment, we estimate roughly 25 percent," he said. "So thesefindings could also have important ramifications for other humandiseases in addition to cancer." Additional References Citations.
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