title: Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics.
abstract: Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/beta-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 beta-catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-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 beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/beta-catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-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 beta-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.
authors.affiliation: INSERM U830, Laboratoire de Génétique et Biologie des Cancers, 75248 Paris Cedex 05, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fattet
authors.forename: Christine
authors.initials: C
authors.lastname: Haberler
authors.forename: Patricia
authors.initials: P
authors.lastname: Legoix
authors.forename: Pascale
authors.initials: P
authors.lastname: Varlet
authors.forename: Arielle
authors.initials: A
authors.lastname: Lellouch-Tubiana
authors.forename: Severine
authors.initials: S
authors.lastname: Lair
authors.forename: Elodie
authors.initials: E
authors.lastname: Manie
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Raquin
authors.forename: Danielle
authors.initials: D
authors.lastname: Bours
authors.forename: Sabrina
authors.initials: S
authors.lastname: Carpentier
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Barillot
authors.forename: Jacques
authors.initials: J
authors.lastname: Grill
authors.forename: Francois
authors.initials: F
authors.lastname: Doz
authors.forename: Stephanie
authors.initials: S
authors.lastname: Puget
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015996:Survival Rate; D051176:beta Catenin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin