Novel Somatic Mutations to PI3K Pathway Genes in Metastatic Melanoma 英文参考文献.docVIP

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Novel Somatic Mutations to PI3K Pathway Genes in Metastatic Melanoma 英文参考文献.doc

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Novel Somatic Mutations to PI3K Pathway Genes in Metastatic Melanoma 英文参考文献

NovelSomaticMutationstoPI3KPathwayGenesin MetastaticMelanoma AustinY.Shull1.,AliciaLatham-Schwark1,2.,PoornemaRamasamy1,KristinLeskoske1,3,DoraOroian1, MarcR.Birtwistle1,PhillipJ.Buckhaults1* 1Georgia Health Sciences University Cancer Center, Georgia Health Sciences University, Augusta, Georgia, United States of America, 2College of Medicine, Medical UniversityofSouthCarolina,Charleston,SouthCarolina,UnitedStatesofAmerica,3DepartmentofMolecularandCellBiology,UniversityofCalifornia,Berkeley,California, UnitedStatesofAmerica Abstract Background:BRAFV600inhibitorshaveofferedanewgatewayforbettertreatmentofmetastaticmelanoma.However,the overall efficacy of BRAFV600 inhibitors has been lower than expected in clinical trials, and many patients have shown resistancetothedrug’seffect.WehypothesizedthatsomaticmutationsinthePhosphoinositide3-Kinase(PI3K)pathway, which promotes proliferation and survival, may coincide with BRAFV600 mutations and contribute to chemotherapeutic resistance. Methods:Weperformedasomaticmutationprofilingstudyusingthe454FLXpyrosequencingplatforminordertoidentify candidatecancergeneswithintheMAPKandPI3Kpathwaysofmelanomapatients.Somaticmutationsofthesescandidate cancergeneswerethenconfirmedusingSangersequencing. Results:Asexpected,BRAFV600mutationswereseenin51%ofthemelanomas,whereasNRASmutationswereseenin19% ofthemelanomas.However,PI3Kpathwaymutations,thoughmoreheterogeneous,werepresentin41%ofthemelanoma, withPTENbeingthehighestmutatedPI3Kgeneinmelanomas(22%).Interestingly,severalnovelPI3Kpathwaymutations were discovered in MTOR, IRS4, PIK3R1, PIK3R4, PIK3R5, and NFKB1. PI3K pathway mutations co-occurred with BRAFV600 mutationsin17%ofthetumorsandco-occurredwith9%ofNRASmutanttumors,implyingcooperativitybetweenthese pathwaysintermsofmelanomaprogression. Conclusions:ThesenovelPI3Kpathwaysomaticmutationscouldprovidealternativesurvivalandproliferativepathwaysfor metastaticmelanomacells.Theythereforemaybepotentialchemotherapeutictargetsformelanomapatientsw