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1、ModernPathology(2012)25,1423–1431&2012USCAP,Inc.Allrightsreserved0893-3952/12$32.001423Proximalcoloncancersandtheserratedpathway:asystematicanalysisofprecursorhistologyandBRAFmutationstatus11231DeepaTPatil,BonnieLShadrach,LisaARybicki,BrandieHLeachandRishKPai12DepartmentofAnatomicPathology,Clevela
2、ndClinic,Cleveland,OH,USA;DepartmentofQuantitative3HealthSciences,ClevelandClinic,Cleveland,OH,USAandDepartmentofGenomicMedicineInstitute,ClevelandClinic,Cleveland,OH,USAAlthoughtheserratedneoplasiapathwayisthoughttogiverisetothemajorityofsporadicmicrosatelliteinstability-high(MSI-H)coloncancer,th
3、eexactproportionofthesetumorsthatarisefromserratedprecursorshasnotbeenfullystudied.Tubularandtubulovillousadenomaswithfeaturesoftheserratedneoplasiapathwayhavebeendescribed,andunlikesessileserratedadenomas,theselesionslackBRAFmutations.ThecontributionoftheseadenomastosporadicMSI-Hcoloncancerisuncl
4、ear.Tothisend,weconductedananalysisofright-sidedsporadicMSI-Handmicrosatellitestable(MSS)coloncancer,withemphasisonprecursorlesions.Overall25%(19/75)ofMSI-Hcoloncancerhadaprecursor,ofwhichonly4wererecognizedhistologicallyasarisingfromasessileserratedadenoma,andtheremainingwerebestclassifiedasadeno
5、mas.Ofthe31(of89)MSScoloncancerswithaprecursor,only1wasasessileserratedadenoma(P¼0.06).HistologicalanalysisoftheprecursoradenomastosporadicMSI-HcoloncancerdemonstratedahighfrequencyofcryptserrationscomparedwithMSScoloncancer(93vs36%,Po0.001).BRAFmutationswerefoundin57/75(76%)sporadicMSI-Hand10/89(
6、11%)MSScoloncancers(Po0.001).MolecularanalysisdemonstratedBRAFmutationsin11/12adenomaand3/3sessileserratedadenomaprecursorsadjacenttoBRAF-mutatedMSI-Hcoloncancer.Similarly,all4precursorstoBRAF-mutatedMSScoloncancerwerealsoBRAFmutated.ThepresenceofBRAFmutationsintheseadenomatousprecursorssuggeststh
7、attheyrepresentsessileserratedadenomaswithcompletecytologicdysplasia.Finally,patientswithsporadicMSI-Hcoloncancerweremorelikelytoharboursynchronoussessileserratedadenomas(20vs8%;P¼0.023).Thisisthelargeststudytori