Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics

Authors

  • Sarah Fattet,

    1. INSERM U830, Laboratoire de Génétique et Biologie des Cancers, 75248 Paris Cedex 05, France
    2. Institut Curie, Centre de Recherche, 26 Rue d'Ulm, 75248 Paris Cedex 05, France
    3. Centre Hospitalier Universitaire Vaudois, Hématologie et Oncologie Pédiatrique, 1011 Lausanne, Switzerland
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  • Christine Haberler,

    1. INSERM U830, Laboratoire de Génétique et Biologie des Cancers, 75248 Paris Cedex 05, France
    2. Institut Curie, Centre de Recherche, 26 Rue d'Ulm, 75248 Paris Cedex 05, France
    3. Institute of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, A-1097 Vienna, Austria
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  • Patricia Legoix,

    1. Institut Curie, Département de Transfert, 26 Rue d'Ulm, 75248 Paris Cedex 05, France
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  • Pascale Varlet,

    1. Centre Hospitalier Sainte Anne, Laboratoire de Neuropathologie, 1 Rue Cabanis, 75014 Paris, France
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  • Arielle Lellouch-Tubiana,

    1. Université Paris Descartes, Faculté de Médecine, 12 Rue de l'Ecole de Médecine, 75006 Paris, France
    2. Hôpital Necker Enfants Malades, Anatomie Pathologique, 149 Rue de Sèvres, 75015 Paris, France
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  • Severine Lair,

    1. Institut Curie, Centre de Recherche, 26 Rue d'Ulm, 75248 Paris Cedex 05, France
    2. INSERM U900, Bioinformatique, 75248 Paris Cedex 05, France
    3. Ecole des Mines ParisTech, 77300 Fontainebleau, France
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  • Elodie Manie,

    1. INSERM U830, Laboratoire de Génétique et Biologie des Cancers, 75248 Paris Cedex 05, France
    2. Institut Curie, Centre de Recherche, 26 Rue d'Ulm, 75248 Paris Cedex 05, France
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  • Marie-Anne Raquin,

    1. Institut Gustave-Roussy, Oncologie Pédiatrique, 39 Rue Camille Desmoulins, 94805 Villejuif, France
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  • Danielle Bours,

    1. Institut Curie, Biostatistiques, 75248 Paris Cedex 05, France
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  • Sabrina Carpentier,

    1. Institut Curie, Centre de Recherche, 26 Rue d'Ulm, 75248 Paris Cedex 05, France
    2. INSERM U900, Bioinformatique, 75248 Paris Cedex 05, France
    3. Ecole des Mines ParisTech, 77300 Fontainebleau, France
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  • Emmanuel Barillot,

    1. Institut Curie, Centre de Recherche, 26 Rue d'Ulm, 75248 Paris Cedex 05, France
    2. INSERM U900, Bioinformatique, 75248 Paris Cedex 05, France
    3. Ecole des Mines ParisTech, 77300 Fontainebleau, France
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  • Jacques Grill,

    1. Institut Gustave-Roussy, Oncologie Pédiatrique, 39 Rue Camille Desmoulins, 94805 Villejuif, France
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  • Francois Doz,

    1. Université Paris Descartes, Faculté de Médecine, 12 Rue de l'Ecole de Médecine, 75006 Paris, France
    2. Institut Curie, Oncologie Pédiatrique, 26 Rue d'Ulm, 75005 Paris, France
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  • Stephanie Puget,

    1. Hôpital Necker Enfants Malades, Neurochirurgie Pédiatrique, 149 Rue de Sèvres, 75015 Paris, France
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  • Isabelle Janoueix-Lerosey,

    1. INSERM U830, Laboratoire de Génétique et Biologie des Cancers, 75248 Paris Cedex 05, France
    2. Institut Curie, Centre de Recherche, 26 Rue d'Ulm, 75248 Paris Cedex 05, France
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  • Olivier Delattre

    Corresponding author
    1. INSERM U830, Laboratoire de Génétique et Biologie des Cancers, 75248 Paris Cedex 05, France
    2. Institut Curie, Centre de Recherche, 26 Rue d'Ulm, 75248 Paris Cedex 05, France
    • INSERM U830, Institut Curie, Centre de Recherche, 26 Rue d'Ulm, 75248 Paris, France.
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  • No conflicts of interest were declared.

Abstract

Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/β-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. We report a series of 72 paediatric medulloblastomas evaluated for β-catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of β-catenin showed extensive nuclear staining (>50% of the tumour cells) in six cases and focal nuclear staining (<10% of cells) in three cases. The other cases either exhibited a signal strictly limited to the cytoplasm (58 cases) or were negative (five cases). CTNNB1 mutations were detected in all β-catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/β-catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear β-catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/β-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5–121.2 months) from diagnosis. All three patients with focal nuclear staining of β-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome, indicating that therapy de-escalation should be considered. International consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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