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Mutations in MLH1 gene and MSI status as molecular characteristics of sporadic colorectal cancer
Čaja, Fabián ; Vodička, Pavel (advisor) ; Kadlecová, Jitka (referee)
Colorectal carcinoma (CRC) is one of the most prevalent malignancies in the Czech Republic. In general, there are two molecular pathways leading to CRC: one is characterized by chromosomal instability, the other by the deficiency in DNA mismatch repair (MMR) genes. MutL homologue 1 (MLH1) gene, a member of the MMR gene-family, represents a key component of the MMR system, responsible for recognition of nucleotide mismatches occurring during DNA replication, and for the recruitment of repair proteins to correct the replication errors. According to literature, somatic mutations in MMR genes, and MLH1 in particular, hallmark sporadic, MMR deficient, CRC cases. We aimed at analyzing somatic events in MLH1 gene and the determination of microsatellite instability (MSI) status in 99 DNA samples from 96 patients with sporadic CRC. Mutations were screened by high resolution melting (HRM) curve analysis. Positive cases in each run were subsequently verified by automated sequencing. Mainly gene variants were found in MLH1 gene: We discovered two new variants, one in exon 2 at position c. 204 C>G, p. Ile68Met (98 C/C, 1C/G) and the other in exon 11 at position c. 973 C>T, p. Arg325Trp (98 C/C, 1 C/T). Only the latter variant c. 973 C>T was identified as somatic mutation. All other variants found in MLH1 gene...
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Neurofibromatosis type 1 and NF1 germline mutations in Czech patients
Bendová, Šárka ; Křepelová, Anna (advisor) ; Kleibl, Zdeněk (referee) ; Kadlecová, Jitka (referee)
Neurofibromatosis type 1 (NF1, MIM 162200) is an autosomal dominant disorder affecting about 1 of 3000 live births, involving many cell types and organs, and associated with an increased risk of malignancy, predominantly of the central and peripheral nervous system 1. Tumour development is caused by inactivation of the NF1 tumour suppressor gene and subsequent cell cycle deregulation 2. Mutational analysis of NF1 is a challenge due to the presence of pseudogenes, large size of the gene, lack of mutational hotspots, and occurrence of a very diverse spectrum of mutations. There is no clear-cut genotype-phenotype correlation allowing accurate prediction of severity of the disorder. Only two mutations have been associated with a particular NF1 phenotype 3,4. This PhD thesis is composed of six publications dealing with NF1. Publications 1 and 6 are focused on NF1 mutation analysis in 67 patients from the Czech Republic. Genotypes and spectra of causal mutations are presented together with phenotypes of the patients and comparison of efficiency of various methods. Sporadic or familial cases with known germline mutation were distinguished by mutational analysis of other family members. This led to a hypothesis that the incidence of sporadic cases could had been overestimated in the past because of overlooked...
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