Disruption of the FA/BRCA pathway in bladder cancer
| Autor: | Michael Schmid, Margaret A. Knowles, Reinhard Kalb, Helmut Hanenberg, Wolfgang A. Schulz, Kornelia Neveling, Richard Friedl, S. Herterich, Andrea R. Florl, F H Hartmann, Carolyn D. Hurst, Claus Steinlein, Detlev Schindler, C Hader, Holger Tönnies, Indrajit Nanda, Holger Hoehn |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Blotting Western Genes BRCA1 Biology FANCF Fanconi anemia FANCG Cell Line Tumor FANCD2 Genetics medicine Humans Genes Tumor Suppressor Fanconi Anemia Complementation Group G Protein Molecular Biology Genetics (clinical) In Situ Hybridization Fluorescence DNA Primers Bladder cancer Base Sequence Mitomycin C Cell Cycle Fanconi Anemia Complementation Group C Protein Genetic Complementation Test FANCF Gene DNA Methylation medicine.disease Molecular biology Urinary Bladder Neoplasms Karyotyping DNA methylation Female |
| Zdroj: | Cytogenetic and genome research. 118(2-4) |
| ISSN: | 1424-859X |
| Popis: | Bladder carcinomas frequently show extensive deletions of chromosomes 9p and/or 9q, potentially including the loci of the Fanconi anemia (FA) genes FANCC and FANCG. FA is a rare recessive disease due to defects in anyone of 13 FANC genes manifesting with genetic instability and increased risk of neoplasia. FA cells are hypersensitive towards DNA crosslinking agents such as mitomycin C and cisplatin that are commonly employed in the chemotherapy of bladder cancers. These observations suggest the possibility of disruption of the FA/BRCA DNA repair pathway in bladder tumors. However, mutations in FANCC or FANCG could not be detected in any of 23 bladder carcinoma cell lines and ten surgical tumor specimens by LOH analysis or by FANCD2 immunoblotting assessing proficiency of the pathway. Only a single cell line, BFTC909, proved defective for FANCD2 monoubiquitination and was highly sensitive towards mitomycin C. This increased sensitivity was restored specifically by transfer of the FANCF gene. Sequencing of FANCF in BFTC909 failed to identify mutations, but methylation of cytosine residues in the FANCF promoter region was demonstrated by methylation-specific PCR, HpaII restriction and bisulfite DNA sequencing. Methylation-specific PCR uncovered only a single instance of FANCF promoter hypermethylation in surgical specimens of further 41 bladder carcinomas. These low proportions suggest that in contrast to other types of tumors silencing of FANCF is a rare event in bladder cancer and that an intact FA/BRCA pathway might be advantageous for tumor progression. |
| Databáze: | OpenAIRE |
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