Scientists have discovered a tumor suppressor gene that appears to beinvolved in the formation of many, if not all, cancer types.The discovery - by researchers at Myriad Genetics Inc., a small,three-year old company in Salt Lake City, and their colleagues at theUniversity of Utah Medical Center - has been hailed as"phenomenally important" by Bert Vogelstein, a cancer gene expert atJohns Hopkins University School of Medicine. And it is also expectedto generate a bonanza of marketing opportunities.In an article to be published in Friday's issue of Science, theresearchers report that the gene, named Multiple Tumor Suppressor 1(MTS1) encodes a protein called p16 that regulates a key step in thecell division process. They note that MTS1 appears to be involved inthe formation of many cancer types, including tumors of the lung,breast, brain, bone, skin (melanoma), bladder, kidney, ovary, andblood. "The research offers strong genetic evidence that p16 plays aleading role in controlling cell division and functions as a generaltumor suppressor," said Mark Skolnick, a professor at the MedicalCenter and Myriad's vice president of research.In normal cells, the MTS1 protein inhibits the activity of a cell cycleenzyme called cyclin-dependent kinase 4, which initiates DNAreplication during the cell division process. In their studies, however,the scientists found that in approximately half the tumor cellsexamined, both copies of the MTS1 gene were deleted, meaning thatthe mechanism that controls the division of cells was absent.In fact, the team found that both copies of MTS1 were deleted in abouthalf of the 290 tumor cell lines screened, representing many differenttypes of cancer."In addition, when we looked in more detail at one cancer type,melanoma, we found that even when one copy of the gene remainedthere was a high frequency - at least 75 percent - of disruptivemutations," Skolnick said.According to C. Alexander Kamb, director of Myriad's genomiclaboratory, MTS1 appears to be the first tumor suppressor gene thatacts at the heart of the cell division cycle. Because MTS1 protein actsdirectly as an enzyme inhibitor, he said, it is fairly easy to mimic withsmall molecule pharmaceuticals. "By contrast," he noted, " the mostcommon tumor suppressor gene identified previously, p53, functionsone step removed from the cell cycle."Nobel laureate Walter Gilbert, who is vice chair of Myriad's board anda Carl M. Loeb University professor at Harvard University, toldBioWorld that the reason the discovery is exciting is because it seemsto be effective in so many tumors."One of the problems with attacking cancer is that there's no uniformproperty that all cells share," Gilbert said. "This discovery is interestingbecause it is a common property. It appears to be a central point ofcontrol. Even though we don't know that it is 100 percent common, ithas been identified in 75 percent of melanomas studied. It seems to beinvolved in the progression of the cell through the cell cycle and seemsto be missing in many and possibly all types of tumors."According to Peter Meldrum, Myriad's president and chief executiveofficer, the company sees substantial therapeutic opportunities in thisdiscovery. "But I don't think you can realistically put a value on thistreatment. It is clearly significant and it clearly has substantialcommercial promise. We will look at the opportunities independentlyand in collaborative alliances with other companies."Meldrum said that for his small, privately-held company, founded in1991, the discovery is an achievement. "It illustrates the gene discoverycapabilities we have. This program from inception through discoverytook only about 18 months."The discovery of MTS1 was made while researchers concentrated theirsearch for a melanoma gene on a region of chromosome 9 known to bea "hot spot" for chromosomal abnormalities. Meldrum noted that thecompany's strategy is to identify a particular disease state and initiate aresearch program around that disease through gene mapping. "We lookfor diseases that have significant commercial market opportunities suchas cancer and heart disease. We believe this is a more focused strategythan merely sequencing DNA in hopes of finding somethingsignificant," he said.Before this discovery, the gene most commonly mutated in cancer wasp53, which is found in 50 percent of all cancers. However, Skolnicktold BioWorld that p16 is easier and simpler to mimic for therapeuticpurposes."The fact that it is expressed in many cells leads one to think that asystemic drug would not be damaging to the body. Because most cellsof the body have p16 in them, it would not be seen as a foreign gene.We are dealing with a deletion, a missing factor, and if you replace themissing factor you have a good therapeutic," Skolnick commented."However, it might be necessary to control the level and the cycle ofthe protein. If you reintroduce it, it may not be healthy to have theprotein all the time in the cell."

-- By Philippa Maister

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