Disruption of the FA/BRCA pathway in bladder cancer

K. Neveling, R. Kalb, A. R. Florl, S. Herterich, R. Friedl, H. Hoehn, C. Hader, F. H. Hartmann, I. Nanda, C. Steinlein, M. Schmid, H. Tönnies, C. D. Hurst, M. A. Knowles, H. Hanenberg, W. A. Schulz, D. Schindler

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)166-176
Number of pages11
JournalCytogenetic and Genome Research
Volume118
Issue number2-4
DOIs
StatePublished - Nov 2007
Externally publishedYes

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Fanconi Anemia
Urinary Bladder Neoplasms
Methylation
Urinary Bladder
Mitomycin
Carcinoma
Neoplasms
Genes
Cell Line
Polymerase Chain Reaction
Chromosome Deletion
Mutation
Cytosine
Rare Diseases
DNA Sequence Analysis
Immunoblotting
Genetic Promoter Regions
DNA Repair
Cisplatin
Drug Therapy

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Neveling, K., Kalb, R., Florl, A. R., Herterich, S., Friedl, R., Hoehn, H., ... Schindler, D. (2007). Disruption of the FA/BRCA pathway in bladder cancer. Cytogenetic and Genome Research, 118(2-4), 166-176. https://doi.org/10.1159/000108297

Disruption of the FA/BRCA pathway in bladder cancer. / Neveling, K.; Kalb, R.; Florl, A. R.; Herterich, S.; Friedl, R.; Hoehn, H.; Hader, C.; Hartmann, F. H.; Nanda, I.; Steinlein, C.; Schmid, M.; Tönnies, H.; Hurst, C. D.; Knowles, M. A.; Hanenberg, H.; Schulz, W. A.; Schindler, D.

In: Cytogenetic and Genome Research, Vol. 118, No. 2-4, 11.2007, p. 166-176.

Research output: Contribution to journalArticle

Neveling, K, Kalb, R, Florl, AR, Herterich, S, Friedl, R, Hoehn, H, Hader, C, Hartmann, FH, Nanda, I, Steinlein, C, Schmid, M, Tönnies, H, Hurst, CD, Knowles, MA, Hanenberg, H, Schulz, WA & Schindler, D 2007, 'Disruption of the FA/BRCA pathway in bladder cancer', Cytogenetic and Genome Research, vol. 118, no. 2-4, pp. 166-176. https://doi.org/10.1159/000108297
Neveling K, Kalb R, Florl AR, Herterich S, Friedl R, Hoehn H et al. Disruption of the FA/BRCA pathway in bladder cancer. Cytogenetic and Genome Research. 2007 Nov;118(2-4):166-176. https://doi.org/10.1159/000108297
Neveling, K. ; Kalb, R. ; Florl, A. R. ; Herterich, S. ; Friedl, R. ; Hoehn, H. ; Hader, C. ; Hartmann, F. H. ; Nanda, I. ; Steinlein, C. ; Schmid, M. ; Tönnies, H. ; Hurst, C. D. ; Knowles, M. A. ; Hanenberg, H. ; Schulz, W. A. ; Schindler, D. / Disruption of the FA/BRCA pathway in bladder cancer. In: Cytogenetic and Genome Research. 2007 ; Vol. 118, No. 2-4. pp. 166-176.
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AU - Hoehn, H.

AU - Hader, C.

AU - Hartmann, F. H.

AU - Nanda, I.

AU - Steinlein, C.

AU - Schmid, M.

AU - Tönnies, H.

AU - Hurst, C. D.

AU - Knowles, M. A.

AU - Hanenberg, H.

AU - Schulz, W. A.

AU - Schindler, D.

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