CTNNB1, AXIN1 and APC expression analysis of different medulloblastoma variants

Abstract

OBJECTIVES:We investigated four components of the Wnt signaling pathway in medulloblastomas. Medulloblastoma is the most common type of malignant pediatric brain tumor, and the Wnt signaling pathway has been shown to be activated in this type of tumor.METHODS:Sixty-one medulloblastoma cases were analyzed for β-catenin gene (CTNNB1) mutations, β-catenin protein expression via immunostaining and Wnt signaling pathway-related gene expression. All data were correlated with histological subtypes and patient clinical information.RESULTS:CTNNB1 sequencing analysis revealed that 11 out of 61 medulloblastomas harbored missense mutations in residues 32, 33, 34 and 37, which are located in exon 3. These mutations alter the glycogen synthase kinase-3β phosphorylation sites, which participate in β-catenin degradation. No significant differences were observed between mutation status and histological medulloblastoma type, patient age and overall or progression-free survival times. Nuclear β-catenin accumulation, which was observed in 27.9% of the cases, was not associated with the histological type, CTNNB1 mutation status or tumor cell dissemination. The relative expression levels of genes that code for proteins involved in the Wnt signaling pathway (CTNNB1, APC, AXIN1 and WNT1) were also analyzed, but no significant correlations were found. In addition, large-cell variant medulloblastomas presented lower relative CTNNB1 expression as compared to the other tumor variants.CONCLUSIONS:A small subset of medulloblastomas carry CTNNB1 mutations with consequent nuclear accumulation of β-catenin. The Wnt signaling pathway plays a role in classic, desmoplastic and extensive nodularity medulloblastoma variants but not in large-cell medulloblastomas.

Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers

“…We detected tumor-specific CTNNB1 mutations in S1, S2, S8, and S9, where b-catenin localization was heterogeneous in one or both tumors. In particular, S1 was shown to harbor the c.100G4A mutation in endometrial and ovarian tumors, 18 in S8 the same c.101G4A mutation was found in both tumors, while S9 ovarian/endometrial cancers harbored a novel c.104T4G mutation. These cases could not be associated with independent primary endometrial and ovarian cancers since a clear b-catenin nuclear pattern was not found and the same somatic mutation was identified in both endometrial and ovarian neoplasias (Table 2).…”

WNT signaling in glioblastoma and therapeutic opportunities

“…Similar to colon cancer, mutations in WNT signaling components (β-catenin, APC, and AXIN1) have been identified in medulloblastoma (a brain tumor primarily originating in the cerebellum). [49][50][51][52][53] Recent largescale genomic studies showed that β-catenin mutations in exon 3, corresponding to its phosphorylation site were found in 18-22% of medulloblastoma cases. 51,52 An additional 5% had mutations in APC or AXIN1.…”

“…51,52 An additional 5% had mutations in APC or AXIN1. 52,53 β-Catenin mutations detected in hepatocellular carcinoma and medulloblastoma led to the disruption of phosphorylation and degradation of β-catenin, resulting in hyperactivation of WNT signaling. 43,44,54 Thus, the mutation status of the above WNT signaling components is an indicator of WNT activation in tumor.…”

Hand1 overexpression inhibits medulloblastoma metastasis

“…Medulloblastomas (MB) are rapidly-growing neuroepithelial tumors of the cerebellum with a tendency to metastasize accounting for about 20% of all brain tumors in children [1,2].…”