Dataset Information

DNA methylation profiling is a method of choice for molecular verification of pediatric WNT-activated medulloblastomas.

ABSTRACT:

Background

Wingless-activated medulloblastoma (WNT MB) represents a well-characterized molecular variant accounting for 10-15% of all MB and is associated with a favorable clinical outcome. Patients with localized WNT MBs could benefit from de-intensification of combined treatment, which would require an accurate diagnosis of these tumors. However, despite the presence of molecular features related with a WNT MB signature (nuclear ß-catenin immunoexpression, CTNNB1 mutation, and monosomy 6), a prompt and reliable diagnostic verification of these tumors is not yet feasible.

Methods

In the current study, we analyzed 78 samples of WNT MB treated in a single institute through genome-wide DNA methylation and targeted next generation sequencing to elaborate an optimal method for WNT MB molecular verification.

Results

We found that DNA methylation profiling discloses significant advantages for molecular diagnostic of WNT MB. All other "routine" methods applied, such as ß-catenin immunohistochemistry, CTNNB1 mutation analysis, and detection of monosomy 6, failed to identify all WNT MB cases. Survival analysis revealed that application of a reduced radiotherapy protocol for WNT MB treatment had no influence on patients' survival. Only one patient died due to local relapse but recurrent tumor was pathologically and molecularly diagnosed as a secondary glioblastoma.

Conclusions

DNA methylation analysis should be considered as a method of choice for further clinically relevant stratification of WNT MB and for correct diagnosis of the recurrent tumors. WNT MB patients with localized disease could benefit from treatment de-intensification.

SUBMITTER: Korshunov A

PROVIDER: S-EPMC6374763 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

DNA methylation profiling is a method of choice for molecular verification of pediatric WNT-activated medulloblastomas.

Korshunov Andrey A Sahm Felix F Zheludkova Olga O Golanov Andrey A Stichel Damian D Schrimpf Daniel D Ryzhova Marina M Potapov Alexander A Habel Antje A Meyer Jochen J Lichter Peter P Jones David T W DTW von Deimling Andreas A Pfister Stefan M SM Kool Marcel M

Neuro-oncology 20190201 2

<h4>Background</h4>Wingless-activated medulloblastoma (WNT MB) represents a well-characterized molecular variant accounting for 10-15% of all MB and is associated with a favorable clinical outcome. Patients with localized WNT MBs could benefit from de-intensification of combined treatment, which would require an accurate diagnosis of these tumors. However, despite the presence of molecular features related with a WNT MB signature (nuclear ß-catenin immunoexpression, CTNNB1 mutation, and monosomy ...[more]

PMID: 30252101

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Project description:Medulloblastoma is the most frequent malignant pediatric brain tumor. Considerable efforts are dedicated to identify markers that help to refine treatment strategies. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favorable patient outcome. We report a series of 72 pediatric medulloblastomas evaluated for beta-catenin immunostaining, CTNNB1 mutations, and studied by 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 tumor cells) in 6 cases and focal nuclear staining (<10% of cells) in 3 cases. The other cases exhibited either a signal strictly limited to the cytoplasm (58 cases) or were negative (5 cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented a strong activation of the Wnt/beta-catenin pathway. Remarkably, 5 out of these 6 tumors showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumors 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) from diagnosis. All three patients with a focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumors represent a distinct molecular subgroup of medulloblastomas with favorable outcome, indicating that therapy de-escalation should be considered. Yet, international consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved. A series of 72 pediatric medulloblastoma tumors has been studied at the genomic level (array-CGH), screened for CTNNB1 mutations and beta-catenin expression (immunohistochemistry). A subset of 40 tumor samples has been analyzed at the RNA expression level (Affymetrix HG U133 Plus 2.0). Correlations between the genomic data, the expression data, the mutational screening, the pathological classification and clinical data is presented in the study. note: aCGH data not submitted to GEO

Dataset Information

DNA methylation profiling is a method of choice for molecular verification of pediatric WNT-activated medulloblastomas.

Background

Methods

Results

Conclusions

Publications

DNA methylation profiling is a method of choice for molecular verification of pediatric WNT-activated medulloblastomas.

Similar Datasets

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