Role of Heterozygous APC Mutation in Niche Succession and Initiation of Colorectal Cancer – A Computational Study 英文参考文献.docVIP

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Role of Heterozygous APC Mutation in Niche Succession and Initiation of Colorectal Cancer – A Computational Study 英文参考文献.doc

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Role of Heterozygous APC Mutation in Niche Succession and Initiation of Colorectal Cancer – A Computational Study 英文参考文献

RoleofHeterozygousAPCMutationinNicheSuccession andInitiationofColorectalCancer–AComputational Study RoschenSasikumar*,JohnRajiRejitha,PonthananiyilKumaranBinumon,MuraleedharanManoj ComputationalModelingandSimulationGroup,NationalInstituteforInterdisciplinaryScienceandTechnology(CSIR),Trivandrum,Kerala,India Abstract Mutations in the adenomatous polyposis coli (APC) gene are found in most colorectal cancers. They cause constitutive activationofproliferativepathwayswhenbothallelesofthegenearemutated.Howeverstudiesonindividualswithfamilial adenomatouspolyposis(FAP)haveshownthatasinglemutatedAPCallelecanalsocreatechangesintheprecancerous coloncrypt,likeincreasednumberofstemcells,increasedcryptfission,greatervariabilityofDNAmethylationpatterns,and higher somatic mutation rates. In this paper, using a computational model of colon crypt dynamics, we evolve and investigateahypothesisontheeffectofheterozygousAPCmutationthatexplainsthesedifferentobservations.Basedon previous reports and the results from the computational model we propose the hypothesis that heterozygous APC mutationhastheeffectofincreasingthechancesforastemcelltodividesymmetrically,producingtwostemcelldaughters. Weincorporatethishypothesisintothemodelandperformsimulationexperimentstoinvestigatetheconsequencesofthe hypothesis.SimulationsshowthatthishypothesislinkstogetherthechangesinFAPcryptsobservedinpreviousstudies. ThesimulationsalsoshowthatanAPC+/2stemcellgetsselectiveadvantagesfordominatingthecryptandprogressingto cancer. This explains why most colon cancers are initiated by APC mutation. The results could have implications for preventing or retarding the onset of colon cancer in people with inherited or acquired mutation of one APC allele. Experimental validation of the hypothesis as well as investigation into the molecular mechanisms of this effect may thereforebeworthundertaking. Citation:SasikumarR,RejithaJR,BinumonPK,ManojM(2011)RoleofHeterozygousAPCMutationinNicheSuccessionandInitiationofColorecta