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Cancer may require simpler genetic mutations than previouslythought by 123wert sdfsf
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Cancer may require simpler genetic mutations than previouslythought |
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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 givesa bigger 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 ishaploinsufficient, then a single gene copy lacks the potency neededto fully restrain tumorigenesis," Elledge explained, who isalso a Howard Hughes Medical Institute Investigator. "So byremoving clusters of haploinsufficient genes all at once, thecancer cell immediately propels its growth forward without havingto wait for the other copies to also be lost." Angelika Amon, a professor of biology at the Massachusetts ofTechnology, said she's surprised by the findings. "We've knownfrom a lot of human syndromes that haploinsufficiency is widespreadin the development of complex multicellular organisms," shesaid. "But these data show it's also critical for individualcells and cell proliferation." 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 todramatically accelerate the acquisition of growth beneficialmutations," Amon said. 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 to40 genes, 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 havesmall effects individually, but large effects in combination,"Elledge said. "Unfortunately, it's not easy to see how to takeadvantage of that 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. "Sothese findings could also have important ramifications for otherhuman diseases in addition to cancer." This work was supported by grants from the NCI/NHGRI funded CancerGenome Atlas (TCGA) project, from the NIH (U54CA143798) to R.B.
andby grants from the NIH, SU2C, and DOD. I am an expert from Furniture & Furnishings, usually analyzes all kind of industries situation, such as kid beach chair , wooden gun cabinets.
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