Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics.
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.
Fattet
Sarah
S
INSERM U830, Laboratoire de Génétique et Biologie des Cancers, 75248 Paris Cedex 05, France.
Haberler
Christine
C
Legoix
Patricia
P
Varlet
Pascale
P
Lellouch-Tubiana
Arielle
A
Lair
Severine
S
Manie
Elodie
E
Raquin
Marie-Anne
MA
Bours
Danielle
D
Carpentier
Sabrina
S
Barillot
Emmanuel
E
Grill
Jacques
J
Doz
Francois
F
Puget
Stephanie
S
Janoueix-Lerosey
Isabelle
I
Delattre
Olivier
O
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*
C495270:CTNNB1 protein, human; D051176:beta Catenin