- Klíčová slova
- rizikové skupiny, mechanismus sebepoškozování, prevence,
- MeSH
- agrese psychologie MeSH
- lidé MeSH
- rizikové faktory MeSH
- sebepoškozování * diagnóza etiologie klasifikace prevence a kontrola psychologie terapie MeSH
- Check Tag
- lidé MeSH
The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in Europe. To evaluate whether sporadic CRCs in Czech patients have specific mutational profiles we analysed somatic genetic changes in known CRC genes (APC, KRAS, TP53, CTNNB1, MUTYH and BRAF, loss of heterozygosity (LOH) at the APC locus, microsatellite instability (MSI), and methylation of the MLH1 promoter) in 103 tumours from 102 individuals. The most frequently mutated gene was APC (68.9% of tumours), followed by KRAS (31.1%), TP53 (27.2%), BRAF (8.7%) and CTNNB1 (1.9%). Heterozygous germline MUTYH mutations in 2 patients were unlikely to contribute to the development of their CRCs. LOH at the APC locus was found in 34.3% of tumours, MSI in 24.3% and MLH1 methylation in 12.7%. Seven tumours (6.9%) were without any changes in the genes tested. The analysis yielded several findings possibly specific for the Czech cohort. Somatic APC mutations did not cluster in the mutation cluster region (MCR). Tumours with MSI but no MLH1 methylation showed earlier onset and more severe mutational profiles compared to MSI tumours with MLH1 methylation. TP53 mutations were predominantly located outside the hot spots, and transitions were underrepresented. Our analysis supports the observation that germline MUTYH mutations are rare in Czech individuals with sporadic CRCs. Our findings suggest the influence of specific ethnic genetic factors and/or lifestyle and dietary habits typical for the Czech population on the development of these cancers.
- MeSH
- adaptorové proteiny signální transdukční genetika MeSH
- běloši genetika MeSH
- beta-katenin genetika MeSH
- DNA-glykosylasy genetika MeSH
- dospělí MeSH
- jaderné proteiny genetika MeSH
- kolorektální nádory genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA genetika MeSH
- mikrosatelitní nestabilita MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádorový supresorový protein p53 genetika MeSH
- promotorové oblasti (genetika) genetika MeSH
- protein familiární adenomatózní polypózy genetika MeSH
- protoonkogenní proteiny B-raf genetika MeSH
- protoonkogenní proteiny genetika MeSH
- ras proteiny genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- zárodečné mutace genetika MeSH
- ztráta heterozygozity genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
The promyelocytic leukemia (PML) gene is an important tumor suppressor gene. We tested the hypothesis that germline disruption of the PML gene may be associated with a cancer predisposition syndrome. Mutation analysis of the PML gene was performed in 111 patients with familial adult cancer or young age-onset adult cancer. These were mostly breast and colon cancer, or colon polyposis patients in whom mutation analyses of the BRCA1, BRCA2, MLH1, MSH2, APC or TP53 genes did not detect a pathogenic germline mutation. Heteroduplex analysis and direct sequencing were used for mutation screening. Mutation-specific methods were designed for frequency determination of novel variants in the general population. No deleterious nonsense or frameshift germline mutations were detected. Several missense single-nucleotide substitutions were found, including two novel missense variants, c.83C>T (p.Thr28Ile) in exon 1 in a 42-year-old breast cancer patient and c.1558C>T (p.Pro520Ser) in exon 6 in a 32-year-old colon cancer patient, that were not detected in 100 and 214 non-cancer persons, respectively. Frequency of the c.2260G>C (p.Ala754Pro) variant in isoform IV of the PML gene was higher in patients with colon polyposis and cancer than in the control group (P = 0.029). In conclusion, germline disruption of the PML gene is probably not associated with a highly penetrant susceptibility to adult-onset breast and colon cancer. Pathogenicity of c.83C>T and c.1558C>T variants in the PML gene is uncertain. Carriers of the c.2260 G>C variant in PMLIV isoform may be at an increased risk of colon polyposis and cancer.
- MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- genotyp MeSH
- jaderné proteiny genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mutační analýza DNA MeSH
- nádorové supresorové proteiny genetika MeSH
- nádory genetika MeSH
- polymerázová řetězová reakce MeSH
- senioři MeSH
- transkripční faktory genetika MeSH
- tumor supresorové geny MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
We present a girl who developed adrenocortical adenoma at the age of 1 year and osteosarcoma at the age of 5 years. There was no history of cancer in her parents and their relatives. However, both tumors were typical for the Li-Fraumeni syndrome (LFS), and the patient met criteria for germline TP53 mutation testing. A mutation in codon 282 (Arg282Trp) was identified in her blood lymphocyte genomic DNA. The substitution was found in neither of her parents, which indicated a possibility of a de novo mutation. Unexpectedly, sequencing of the DNA of the patient repeatedly showed allelic imbalance in favor of the normal allele. This observation prompted us to investigate the putative somatic mosaicism in the patient consisting of normal cells and cells heterozygous for the mutation. The imbalance was also examined in two other non-invasively sampled tissues, buccal cells, and cells from the urine sediment, and sequencing was confirmed with two other independent methods. While the findings in blood and the urine sediment were similar, in buccal cells both alleles were present in equal amounts. The allele ratio in lymphocytes was consistent with a mosaic where about 2/3 of cells carried two normal alleles and only 1/3 was heterozygous for the mutation. Despite the mosaicism the girl developed two early childhood tumors of mesodermal origin, and her phenotype was thus not milder than that of other germline TP53 mutation carriers. To our knowledge this is the first description of somatic mosaicism for a de novo TP53 mutation in LFS. (c) 2008 Wiley-Liss, Inc.
- MeSH
- alely - nerovnováha MeSH
- financování organizované MeSH
- lidé MeSH
- Liův-Fraumeniho syndrom genetika MeSH
- missense mutace MeSH
- mozaicismus MeSH
- nádorový supresorový protein p53 genetika MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- rodokmen MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
