Microsatellite Instability in Colorectal Cancer A.ppt

microsatelliteinstabilityinsporadiccolorectalcancer aretrospectivestudy kimberleyslowthertraineeprojectwestmidlandsregionalgeneticslaboratory colorectalcancer 35 000diagnosedperyeartreatmentandprognosisdependupontumourstage causesofcrc sporadic75 raresyndromes 1 fap1 hnpcc5 familial19 geneticpathwaysincrc microsatelliteinstability msi h deficiencyindnamismatchrepair mmr hnpcc msh2 mlh1 msh6 pms2 15 sporadic hypermethylationofmlh1promoter chromosomalinstability cin apc tp53 kras lossofheterozygosity aneuploiddnacontentcpgislandmethylatorphenotype cimp methylationofcpgislandsinpromoterregionsoftumoursuppressorgenessporadiccrcsdemonstratingmsiareasubset microsatelliteinstability comparisonofsporadicmsi hwithhnpcctumours botharemsi handproximallylocatedbutsporadicmsi h greaterpredilectionfortheproximalcolonhigherfrequencyofbrafmutationslowerfrequencyofkrasmutationsmoreagerelatedmorecommoninfemalesoriginatefromserratedpolypshnpcctumoursoriginatefromadenomas ras raf mek erkpathway brafserine threoninespecifickinase40 sporadicmsi htumoursnotpresentinhnpcccommonmutation 90 isv600e krasgtpase90 mutationsincodons12and1330 40 sporadicmsscrc40 hnpcc regulatesgrowth differentiationandapoptosis msiandprognosis msiincrcisapositiveprognosticindicatorbetterfive yearrateofoverallsurvivalthanmsstumourslesslikelytometastasisewhy enhancedmutationrateinducesaburdennotcompatiblewithtumourcellsurvivalabnormalpeptidesproducedelicitantitumourimmuneresponsesthatlimittumourgrowth treatmentofcrc dictatedbystagestagei surgeryalonestageii iii iv adjuvanttherapylessclearcutwithstageiipatientsreviewedonindividualbasischemotherapydrugs5 fluorouracil folinicacid 5fu fa tostageiiandiiipatients5fu faandoxaliplatintostageivandfitterstageiiandiiipatients msiandchemotherapy resistanceofmsi hcrcto5fuiswelldocumentedmsspatientshaveincreasedsurvivalwith5fumsi hpatientsdonothaveimprovedsurvivalfollowingtreatmentwhyhave5futreatmentifthereisnobenefit oxaliplatintherapynotaffectedbylossofmmrinformationaboutmsistatuscouldimpacttreatment decisionofwhetherornottooptforadjuvanttherapyallocationpatientstooxaliplatintherapy projectaim investigatewhethermicrosatelliteanalysisofsporadiccolorectalcancerwouldbeavaluableservicetoofferinfutureinordertotailorpatienttreatment methods msistatusofpatientswithlocallyadvanced treatablesporadic absenceoffamilyhistory crc41 departmentofsurgeryepithelialresearchgroup32 departmentofhistopathology7microsatellitemarkersmsi hifinstabilitypresentat2ormoremarkersmsi lifinstabilitypresentat1markeranalysedmsidatainrelationto ageatdiagnosisgenderbrafexon15mutationkrascodon12and13mutation 41 73 tumoursitetumourdifferentiation results microsatellitestatusandage onaveragepatientsdemonstratingmsiintheirtumourswereyoungerbutthiswasnotstatisticallysignificantofthe14patientsamplesdemonstratingmsi 7wereolderthan70atdiagnosisusuallyoptnottobetreatedwithadjuvanttherapy msistatuscouldbeusedtohelpmakethisdecision plus minusvaluesaremeans sd results microsatellitestatusandgender morefemalesamplesdemonstratedmsi hbutthiswasnotstatisticallysignificant results microsatellitestatusandtumourdifferentiation msi htumoursmorepoorlydifferentiatedthanmssormsi ltumours results microsatellitestatusandtumoursite msi hassociatedwithlocalisationoftumourtotheproximalcolon results microsatellitestatusandbraf krasmutations krasmutationsandbrafmutationsweremutuallyexclusivemssandmsi ltumourshadahigherfrequencyofkrasmutationsmsi htumourshigherfrequencyofbrafmutations discussion whatarethebenefitsofmsianalysisforsporadiccrc improvedpatientcaremsi hnotgivenunnecessarytreatment 5 fu msi hallocatedtomoreeffectivetreatments oxaliplatin costbenefitreducedchemotherapy perhapsnotalltumoursweresporadicethicalimplicationspossibilitythathnpccpatientsincludedonly14 msi hsamplescontainedbrafmutationsrecommendthatpatientsarecounselled futuredevelopments prospectivestudytreatmentvsnotreatment unethicalcomplicatedbywideuseofoxaliplatinoxaliplatinvs5fuinthefuturejustofferoxaliplatintherapytomsi hpatients conclusion techniquesavailabletoputasystemintoplacetooffermsianalysisofsporadiccolorectaltumourstailorpatienttreatmentdependingupontumourstage microsatellitestatusandage acknowledgements westmidlandsregionalgeneticslaborato