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Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract

Oncogene volume 25, pages 2113–2118 (2006)Cite this article

Abstract

A subset of upper urinary tract urothelial cell carcinomas (UUC), arising sporadically or as a manifestation of hereditary non-polyposis colorectal cancer, displays microsatellite instability (MSI). MSI tumours are characterized by defective mismatch repair and accumulation of frameshift mutations in numerous genes harbouring repeats in their coding sequences. We have evaluated the incidence of MSI in UUC and the intratumoral distribution of mutations in 13 candidate target genes. A total of 58 unselected UUC were screened for MSI using the panel of five mononucleotide markers recently recommended by the National Cancer Institute for a precise MSI assessment. Four tumours displayed MSI (7%), among which at least three had alterations in the genes MSH3, BAX, MRE11, RAD50. Mutations in genes involved in key cellular pathways (ATR, DNA-PKcs, MBD4, TCF-4, MSH6, and BLM) were further detected. BAX and MRE11 mutations tend to present homogeneously within the three MSI UUC. Immunohistochemistry (MLH1, MSH2, MSH6) showed that loss of mismatch repair protein expression occurred in all MSI UUC defining the gene defect and that MRE11 and RAD50 mutations were associated with their concomitant loss expression. In conclusion, MSI UUC represent a small proportion of UUC in which BAX and MRE11 mutations are frequent and may play a role early in UUC tumorigenesis.

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Acknowledgements

We thank Dr Alex Duval for helpful discussions, Michèle Oliveiro and Sandrine Villeboux for their expert technical assistance. We also thank Professor Jean-François Fléjou for performing immunohistochemical analyses of mismatch repair proteins. Pierre Mongiat-Artus received support from the ‘Association Française d’Urologie’. Catherine Miquel was supported by the ‘Fondation pour la Recherche Médicale’. This research was supported by a grant from the ‘Association pour la Recherche sur le Cancer’ (No. 4683 to FP)

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Authors and Affiliations

  1. Department of Urology, University Paris VII, Saint-Louis Hospital, Paris, France

    P Mongiat-Artus & P Teillac

  2. Centre National de la Recherche Scientifique UPR 2169, ‘Genetic Instability and Cancer’, Villejuif, France

    C Miquel & F Praz

  3. Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands

    M Van der Aa & T van der Kwast

  4. INSERM, U434, Centre d'Etude du Polymorphisme Humain, Paris, France

    O Buhard & R Hamelin

  5. Department of Biochemistry, CNRS UPR 9051, Saint-Louis Hospital, Paris, France

    H Soliman

  6. Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands

    C Bangma

  7. Department of Pathology, INSERM, U728, Saint-Louis Hospital, Paris, France

    A Janin

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  1. P Mongiat-Artus
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  2. C Miquel
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Correspondence to P Mongiat-Artus.

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Mongiat-Artus, P., Miquel, C., Van der Aa, M. et al. Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract. Oncogene 25, 2113–2118 (2006). https://doi.org/10.1038/sj.onc.1209229

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