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In an article published online May 9 in Nature, the authors provide the first high-resolution view of the genomiclandscape of human melanoma tumors. Previous genetic analyses havefocused on the exomes of many types of cancer tumors, concentratingon the tiny fraction of the genome that provides the genetic codefor producing proteins. Whole genomes contain a wealth of geneticinformation, and by sequencing and analyzing 25 metastatic melanomatumors -- a significant technical and computational feat --scientists can learn vastly more about the variety of geneticalterations that matter in melanoma. "Sequencing the whole genome certainly adds a richness ofdiscovery that can't be fully captured with a whole exome,"said Levi A. Garraway, a senior associate member of the BroadInstitute, an associate professor at Dana-Farber Cancer Instituteand Harvard Medical School, and co-senior author of the paper. "By looking across the entire genome you can more accuratelydetermine the background mutation rate and the different classes ofmutations, and more confidently describe the pattern ofultraviolet-induced mutagenesis in melanoma," said Michael F.Berger, co-first author of the paper. He worked in the Broad'scancer genome analysis group and with Garraway as a researchscientist and computational biologist before moving to MemorialSloan-Kettering Cancer Center. When the scientists explored the whole genome data generated andanalyzed at the Broad, they found that the rates of geneticmutations rose along with chronic sun exposure in patients,confirming the role of sun damage in disease development. "Whole-genome analysis of human melanoma tumors shows for thefirst time the existence of many structural rearrangements in thistumor type," said Lynda Chin, a senior associate member of theBroad and co-senior author of the paper. Formerly at Dana-Farberand Harvard Medical School, she is now chair of the Department ofGenomic Medicine at the University of Texas MD Anderson CancerCenter. As expected, the scientists detected known BRAF and NRAS mutations in 24 of the 25 tumors. Both genes are involved insending signals important in cell growth. One other gene leaped out: PREX2, previously implicated in breast cancer for blocking atumor-suppressor pathway, was altered in 44 percent of patients. Ina larger validation cohort of 107 tumors, the frequency of themutation was 14 percent. PREX2 is mutated in a convergence of genetic disruption that appears toaccelerate tumor development. Its mutations occurred not just athot spots that typically turn on an oncogene, a type ofcancer-causing gene, and drive cancer forward. The alterations werealso scattered across the length of the gene in a pattern typicallyseen when another type of cancer-causing gene, known as tumorsuppressors, are turned off. "The pattern of mutations here looks a lot more like a tumorsuppressor gene, but from the functional experiments, it behavedmore like an oncogene," Berger said. When PREX2 functions normally, it interacts with the protein PTEN. PTEN iswell known as a tumor suppressor, controlling growth in normalcells. Mouse experiments in Chin's lab at Dana-Farber showed that PREX2 mutations spurred tumor growth in ways that are not fullyunderstood. "We still can't say we know exactly how it works,"Garraway said. "PREX2 may be in a very interesting new category of mutated cancer genesthat point us to at least one and maybe more pathways that would beworth targeting therapeutically in melanoma." The identification of PREX2 may be the tip of the iceberg. "New melanoma genes remain to be discovered by this unbiasedapproach, as illustrated by the discovery of PREX2 and the demonstration of its oncogenicity in vivo," saidChin. Other Broad, Dana-Farber, and Harvard researchers who contributedto this work include Eran Hodis, Timothy P. Heffernan, YonathanLissanu Deribe, Michael S. Lawrence, Alexei Protopopov, ElenaIvanova, Ian R. Watson, Elizabeth Nickerson, Papia Ghosh, HaileiZhang, Rhamy Zeid, Xiaojia Ren, Kristian Cibulskis, Andrey Y.Sivachenko, Nikhil Wagle, Carrie Sougnez, Robert Onofrio, LaurenAmbrogio, Daniel Auclair, Timothy Fennell, Scott L. Carter, YotamDrier, Petar Stojanov, Meredith A. Singer, Douglas Voet, Rui Jing,Gordon Saksena, Jordi Barretina, Alex H. Ramos, Trevor J. Pugh,Nicolas Stransky, Melissa Parkin, Wendy Winckler, Scott Mahan,Kristin Ardlie, Jennifer Baldwin, Jennifer Wargo, Matthew Meyerson,Stacey B. Gabriel, Todd R. Golub, Eric S. Lander, and Gad Getz.Researchers from University Hospital Essen, Weizmann Institute ofScience, and Medical University of Vienna also contributed to thework. The work was supported by the National Human Genome ResearchInstitute, National Cancer Institute, FWF-Austrian Science Fund,NIH Director's New Innovator Award, and the Burroughs-WellcomeFund. The e-commerce company in China offers quality products such as Plastic Electronic Enclosures , Silicone Rubber Gasket Manufacturer, and more. For more , please visit Custom Plastic Injection Molding today!
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