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1、Microsatellite Instability in Sporadic Colorectal Cancer:A Retrospective Study,Kimberley SlowtherTrainee ProjectWest Midlands Regional Genetics Laboratory,Colorectal Cancer,35,000 diagnosed per yearTreatment and prognosis depend upon tumour stage,Causes of CRC,Sporadic 75%,Rare Syndromes1%,FAP 1%,HN
2、PCC 5%,Familial 19%,Genetic Pathways in CRC,Microsatellite Instability(MSI-H)Deficiency in DNA mismatch repair(MMR)HNPCC(MSH2,MLH1,MSH6,PMS2)15%sporadic(hypermethylation of MLH1 promoter)Chromosomal Instability(CIN)APC,TP53,KRAS,Loss of Heterozygosity,aneuploid DNA contentCpG Island Methylator Pheno
3、type(CIMP)Methylation of CpG islands in promoter regions of tumour suppressor genesSporadic CRCs demonstrating MSI are a subset,Microsatellite Instability,Comparison of Sporadic MSI-H with HNPCC Tumours,Both are MSI-H and proximally locatedBUT Sporadic MSI-H:-Greater predilection for the proximal co
4、lonHigher frequency of BRAF mutationsLower frequency of KRAS mutationsMore age relatedMore common in females Originate from serrated polypsHNPCC tumours originate from adenomas,RAS-RAF-MEK-ERK Pathway,BRAFSerine-threonine specific kinase40%sporadic MSI-H tumoursNot present in HNPCC Common mutation(9
5、0%)is V600E,KRASGTPase90%mutations in codons 12 and 1330-40%sporadic MSS CRC40%HNPCC,Regulates growth,differentiation and apoptosis,MSI and Prognosis,MSI in CRC is a positive prognostic indicator Better five-year rate of overall survival than MSS tumours Less likely to metastasise Why?Enhanced mutat
6、ion rate induces a burden not compatible with tumour cell survivalAbnormal peptides produced elicit antitumour immune responses that limit tumour growth,Treatment of CRC,Dictated by stageStage I:surgery aloneStage II,III+IV:adjuvant therapyLess clear cut with Stage IIPatients reviewed on individual
7、basisChemotherapy Drugs5-fluorouracil/folinic acid(5FU/FA)to Stage II and III patients5FU/FA and Oxaliplatin to Stage IV and fitter Stage II and III patients,MSI and Chemotherapy,Resistance of MSI-H CRC to 5FU is well documentedMSS patients have increased survival with 5FUMSI-H patients do not have
8、improved survival following treatment Why have 5FU treatment if there is no benefit?Oxaliplatin therapy not affected by loss of MMRInformation about MSI status could impact treatment:-Decision of whether or not to opt for adjuvant therapyAllocation patients to oxaliplatin therapy,Project Aim,Investi
9、gate whether microsatelliteanalysis of sporadic colorectal cancer would be a valuable service to offer in future in order to tailor patient treatment,Methods,MSI status of patients with locally advanced,treatable sporadic(absence of family history)CRC 41 Department of Surgery Epithelial Research Gro
10、up32 Department of Histopathology7 microsatellite markers MSI-H if instability present at 2 or more markersMSI-L if instability present at 1 markerAnalysed MSI data in relation to:-Age at diagnosis Gender BRAF exon 15 mutationKRAS codon 12 and 13 mutation(41/73)Tumour siteTumour differentiation,Resu
11、lts:Microsatellite Status and Age,On average patients demonstrating MSI in their tumours were younger but this was not statistically significantOf the 14 patient samples demonstrating MSI,7 were older than 70 at diagnosisUsually opt not to be treated with adjuvant therapy;MSI status could be used to
12、 help make this decision,Plus-minus values are means SD.,Results:Microsatellite Status and Gender,More female samples demonstrated MSI-H but this was not statistically significant,Results:Microsatellite Status and Tumour Differentiation,MSI-H tumours more poorly differentiated than MSS or MSI-L tumo
13、urs,Results:Microsatellite Status and Tumour Site,MSI-H associated with localisation of tumour to the proximal colon,Results:Microsatellite Status and BRAF/KRAS Mutations,KRAS mutations and BRAF mutations were mutually exclusiveMSS and MSI-L tumours had a higher frequency of KRAS mutationsMSI-H tumo
14、urs higher frequency of BRAF mutations,Discussion,What are the benefits of MSI analysis for sporadic CRC?Improved patient careMSI-H not given unnecessary treatment(5-FU)MSI-H allocated to more effective treatments(Oxaliplatin)?Cost BenefitReduced chemotherapy?Perhaps not all tumours were sporadicEth
15、ical ImplicationsPossibility that HNPCC patients includedOnly 14%MSI-H samples contained BRAF mutations Recommend that patients are counselled,Future Developments,Prospective studyTreatment vs no treatment?UnethicalComplicated by wide use of oxaliplatinOxaliplatin vs 5FUIn the future just offer oxal
16、iplatin therapy to MSI-H patients,Conclusion,Techniques available to put a system into place to offer MSI analysis of sporadic colorectal tumoursTailor patient treatment depending upon tumour stage,microsatellite status and age,Acknowledgements,West Midlands Regional Genetics LaboratoryFiona MacdonaldJennie BellKerry WallUniversity of Birmingham Department of Surgery Epithelial Research GroupDion MortonGermaine CaldwellUniversity Hospital of Birmingham Histopathology DepartmentPhilippe TaniereBrendan OSullivanGraham Caine,
