隱窩異常病灶(ACF)分子遺傳學(xué)及與大腸癌關(guān)系的研究.pdf

1、復(fù)旦大學(xué)博士學(xué)位論文隱窩異常病灶（ACF）分子遺傳學(xué)及與大腸癌關(guān)系的研究姓名：袁平申請(qǐng)學(xué)位級(jí)別：博士專(zhuān)業(yè)：病理學(xué)與病理生理學(xué)指導(dǎo)教師：張錦生2001.5.1隱窩異常病灶分子遺傳學(xué)及與大腸癌關(guān)系的研究英文摘要AmoleculargeneticstudyonaberrantcryptfocianditsimplicationincarcinogenesisofcolorectumAbstruct【AimlThegeneticdiversit

2、yofKrasandAPCgenesandlOSSofheterozygosity(LOH)andinstabilityofmicrosatellite(MSI)atmultiplelociinaberrantcryptfoci(ACF)，adenomaandcarcinomaofcolorectumwerestudiedinordertoexploretheimplicationofACFandthemoleculargeneticb

3、asesofitsrelationshipwithcolorectalcarcinoma[MethodslGenomicDNAwasextractedrespectivelyfrommicrodissectednormalmucosaglands(35cases)，ACFs(34cases)，sporadicadenomas(15cases)andcarcinomas(35cases)TheproductsofPCRusingtheex

4、tractedgenomicDNAastemplateswereemployed：f1)todirectlyassaysequencesofDNAfordetectingthemutationsatcodon12，13，61ofKrasgeneandthemutationclusterregionofexon15ofAPCgene；(2)toanalyseLOHandMSIatmicrosatelliteloci18q12，18q21，

5、5q12，5q21，3p21，2p16，17q21，17ql1，and1lpl3bymeansofABIandGeneScansoftwareanalysis『Resnltsl(1)ThemutationalratesofKrasgeneinACF，adenomaandcarcinomaarecomparableApointmutation(GGC—GAC、atcodon13inACFwasidentifiedexceptpointmu

6、tation(GGT—，GAT、atcodon12whichwasalsofoundinadenomaandcarcinoma；(2)MostoftheACFwithK—rasmutationsarelocatedatsigmoidcolonandrectumtheirclinicalpathologicalcharacteristicsaresimilartotheCOexistingcarcinomasThecarcinomaswi

7、thmutationatcodon12aremoreaggressive(3)APCgenemutationwasinfrequentlydetectedinACF，however，adenomaandcarcinomahadalmostthesamemutationrateat姆CgeneandmuchhigherthanACF；(4)TherateofLOHinACF(418％1islessthanthatincarcinoma(6

8、857％)TheprofileofLOHratesatloci18q12，5q12，3p21，17q2l，17ql1，1lpl3and2p16inACFisresemblingtothoseincareinomawiththeratesatleading5lOCihigherthanthoseatremaining2lociHowevertherateatlocus18q21and5q21inACFiSmuchlessthanthati

9、ncarcinoma(5)InthoseACFwithLOH，theirCO—existingcarcinomasareusuallypolypoidtypeandlocatedatsigmoidcolonandrectum(6)MSlwasidentifiedinonly4in34ACFs，itsimplicationneedsfurtherdisclosed[ConclusionslThemorphologyofACFisdiffe

10、rentfromadenomaandcarcinomaandsomeofgeneticdiversityatgenesstudiedinACFisdistinctfromadenomabutcomparabletocarcinomaThatmayimply：(1)ACFmightbetheearliestlesionappearingevenbeforeadenomaduringcarcinogenesisofcolorectum；(2

11、)thereispossibilitythatnormalmucosaACFcarcinomapathwayexistsincolorectalcarcinogenesis；(3)thealterationofAPCgeneiSnotnecessarytheveryearlyeventincolorectalcarcinogenesisKeywords：colorectalcarcinoma；aberrantcryptfoci(ACF)