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13.
Mikrosatelitna nestabilnost v kancerogenezi : molekularno genetski mehanizmi in pomen pri odkrivanju bolnikov s HNPCC sindromom : doktorska disertacija
Potočnik, Uroš, 1969-
The aim of our study was to analyze the molecular genetic mechanisms involved in initiation and progression of ColoRectal Cancer (CRC). 400 patients with unsetected primary CRC participated in this ...study. Tumors were firstly analyzed for MicroSatellite Instability (MSI). All tumors with high microsatellite instability (MSI-H) were further analysed for different inactivating mechanisms of MisMatch Repair (MMR) genes and other candidate tumor suppresser genes. We performed mutational analysis using PCR-conformational analysis. For methylation analysis DNA was treated with bisulphite and sequenced. Loss of heterozigosity was performed with microsatellite markers and intragenic polymorphisms. Microsatellite analysis of 345 unselected primary CRC revealed 35 (10%) tumors with high microsatellite instability (MSI-H). We identified 6 (17%) MSI-H tumors with germline mutation in the hMLH9 (4/6) or hMSH2 (2/6), the major MMR genes. Thisapproach allowed us to identify 6 Slovenian families with Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and to estimate the minimal incidence of HNPCC in a Slovenian population to at least 1,7 % of all CRC. Of 6 germlinemutations, 3 were novel and so far specific for Slovenian population and the other 3 were previously identified also in other populations. We further showed a different way of inactivation of MMR genes in sporadic MSI-H tumors versus MSI-H tumors from HNPCC patients. The HNPCC MSI-H tumors are mainly caused by germline MMR mutation on one allele and somatic MMR mutation or LOH on the other allele. The majority of sporadic MSI-H tumors were caused by biallelic hypermethylation of hMLH1 promoter. Based on these results we designed molecular genetic approach for HNPCC screeningČ MSI analysis of newlydiagnosed primary CRC followed by methylation analysis of hMLH9 promoter and loss of heterozigosity in MSI-H tumors. (Abstract truncated at 2000 characters)
Type of material - dissertation
; adult, serious
Publication and manufacture - Ljubljana : [U. Potočnik], 2001
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