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dc.contributor.authorJohannsdottir, J T
dc.contributor.authorJonasson, J G
dc.contributor.authorBergthorsson, J T
dc.contributor.authorAmundadottir, L T
dc.contributor.authorMagnusson, J
dc.contributor.authorEgilsson, V
dc.contributor.authorIngvarsson, S
dc.date.accessioned2010-08-23T13:50:42Z
dc.date.available2010-08-23T13:50:42Z
dc.date.issued2000-01-01
dc.date.submitted2010-07-23
dc.identifier.citationInt. J. Oncol. 2000, 16(1):133-9en
dc.identifier.issn1019-6439
dc.identifier.pmid10601558
dc.identifier.urihttp://hdl.handle.net/2336/110143
dc.description.abstractWe have investigated microsatellite instability (MSI) in colorectal, gastric, endometrial and ovarian cancer as a result of mismatch repair (MMR) deficiency. We detected frameshift mutations in several genes that carry short repeated sequences and are important in cell fidelity and growth control; hMSH3, hMSH6, BAX, IGFIIR, TGFbetaIIR, E2F4 and BRCA2. Accumulation of mutations was heterogeneous and mainly restricted to tumours showing MSI at several loci (MSI-H). Both insertions and deletions were evident and occasional intratumour heterogeneity was evident with more than one different additional allele in the tumour. Most MSI-H tumours had acquired mutations in more than one gene and longer repeated sequences were more frequently targets for mutations. The TGFbetaIIR gene was mutated in 62%, the hMSH3 gene in 43%, the E2F4 gene in 35%, the hMSH6 in 32%, the BAX gene in 32%, the IGFIIR gene in 26%, and the BRCA2 gene in 2% of the MSI-H tumours. Homozygous mutations or mutation of both alleles were evident in all genes except BRCA2, in total 23/105 mutated cases, varying from 7% for BAX to 50% for E2F4. E2F4 mutations were exclusively found in colon tumours and E2F4 polymorphisms was found in 8% of cases. No difference in mutation prevalence was noted between cancer types apart from TGFbetaIIR mutations, which were frequently found in colon and gastric tumours but not in endometrial tumours, suggesting that endometrial tumours progress by a different route where TGFbetaIIR mutations are less favourable.
dc.language.isoenen
dc.publisherD.A. Spandidosen
dc.subject.meshAgeden
dc.subject.meshBRCA2 Proteinen
dc.subject.meshBase Pair Mismatchen
dc.subject.meshCell Transformation, Neoplasticen
dc.subject.meshColorectal Neoplasms, Hereditary Nonpolyposisen
dc.subject.meshDNA Ligasesen
dc.subject.meshDNA Repairen
dc.subject.meshDNA-Binding Proteinsen
dc.subject.meshHumansen
dc.subject.meshMicrosatellite Repeatsen
dc.subject.meshMiddle Ageden
dc.subject.meshMultidrug Resistance-Associated Proteinsen
dc.subject.meshNeoplasm Proteinsen
dc.subject.meshPhenotypeen
dc.subject.meshProtein-Serine-Threonine Kinasesen
dc.subject.meshProto-Oncogene Proteinsen
dc.subject.meshProto-Oncogene Proteins c-bcl-2en
dc.subject.meshReceptor, IGF Type 2en
dc.subject.meshReceptors, Transforming Growth Factor betaen
dc.subject.meshTranscription Factorsen
dc.subject.meshbcl-2-Associated X Proteinen
dc.titleThe effect of mismatch repair deficiency on tumourigenesis; microsatellite instability affecting genes containing short repeated sequencesen
dc.typeArticleen
dc.contributor.departmentDepartment of Pathology, National University Hospital, Reykjavik, Iceland.en
dc.identifier.journalInternational journal of oncologyen
html.description.abstractWe have investigated microsatellite instability (MSI) in colorectal, gastric, endometrial and ovarian cancer as a result of mismatch repair (MMR) deficiency. We detected frameshift mutations in several genes that carry short repeated sequences and are important in cell fidelity and growth control; hMSH3, hMSH6, BAX, IGFIIR, TGFbetaIIR, E2F4 and BRCA2. Accumulation of mutations was heterogeneous and mainly restricted to tumours showing MSI at several loci (MSI-H). Both insertions and deletions were evident and occasional intratumour heterogeneity was evident with more than one different additional allele in the tumour. Most MSI-H tumours had acquired mutations in more than one gene and longer repeated sequences were more frequently targets for mutations. The TGFbetaIIR gene was mutated in 62%, the hMSH3 gene in 43%, the E2F4 gene in 35%, the hMSH6 in 32%, the BAX gene in 32%, the IGFIIR gene in 26%, and the BRCA2 gene in 2% of the MSI-H tumours. Homozygous mutations or mutation of both alleles were evident in all genes except BRCA2, in total 23/105 mutated cases, varying from 7% for BAX to 50% for E2F4. E2F4 mutations were exclusively found in colon tumours and E2F4 polymorphisms was found in 8% of cases. No difference in mutation prevalence was noted between cancer types apart from TGFbetaIIR mutations, which were frequently found in colon and gastric tumours but not in endometrial tumours, suggesting that endometrial tumours progress by a different route where TGFbetaIIR mutations are less favourable.


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