Molecular characterization of Wnt pathway and function of β-catenin overexpression in medulloblastoma cell lines

Geron, Lenisa; Salomão, Karina Bezerra; Borges, Kleiton Silva; Andrade, Augusto Faria; Corrêa, Carolina Alves Pereira; Scrideli, Carlos Alberto; Tone, Luíz Gonzaga

doi:10.1007/s10616-018-0260-2

Cited by 11 publications

(13 citation statements)

References 44 publications

(64 reference statements)

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“…Up to 30-40% of G4 MB patients have metastases at diagnosis and are treated as high risk (7,49). Adults with G4 MBs have a significantly poorer prognosis compared to the SHH-or WNT-subtypes (22,23,57). In our cohort, the male/female ratio was close to 50:50 in the G4 subgroup, arguing against a high gender preference in the SA population.…”

Section: Discussionmentioning

confidence: 58%

“…G4 MBs are the most prevalent biological subtype, comprising ∼40% of all MB tumors, which predominantly occur in those aged 3 to 16 years (22,23,50,57,58). G4 is reportedly 3fold more frequent in males than females across all age groups, with an intermediate prognosis and 5-years survival reaching ∼80% with standard therapy, although non-metastatic tumors with chromosome 11 loss have an excellent prognosis, with > 90% survival (18,44,59).…”

Section: Discussionmentioning

confidence: 99%

“…To investigate sample stability, samples were assessed using the successor Methylation BeadChip (EPIC) array or whole-genome bisulfite sequencing. Established molecular characteristics of the WNT subgroup (CTNNB1 mutations, chromosome 6 loss), MYC and MYCN amplifications, and chromosome 17 status were assessed as previously described (13,(21)(22)(23)(24)27). Each MB subgroup was assessed by immunohistochemistry and mRNA expression signature assays.…”

Section: Dna Methylation Profiling Of the Saudi Mb Cohortmentioning

confidence: 99%

“…No events were observed in the WNT group. It is therefore advised that patients with WNT-MB in SA be considered for the controlled reduction of treatment to minimize radiation and chemotherapy side effects (21)(22)(23)(24)(25).…”

Section: Methylation Subgroups Can Dictate Survival Outcomes For Sa-mmentioning

confidence: 99%

“…These distinct genetic features lead to diverse clinical outcomes (5,7,18,20). Patients with WNT-MB have an excellent prognosis with current therapy schemes (5-years event-free survival ≥90%) and are considered for the controlled reduction of treatment to minimize radiation and chemotherapy exposure (21)(22)(23)(24)(25). The prognoses of SHH-activated MBs are less favorable; SHH-MBs have an intact blood-brain barrier (BBB) and are less responsive to chemotherapy compared to WNT-MBs (22,26,27).…”

Section: Introductionmentioning

confidence: 99%

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Methylation Profiling of Medulloblastoma in a Clinical Setting Permits Sub-classification and Reveals New Outcome Predictions

et al. 2020

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Medulloblastoma (MB) is the most common childhood malignant brain tumor and is a leading cause of cancer-related death in children. DNA methylation profiling has rapidly advanced our understanding of MB pathogenesis at the molecular level, but assessments in Saudi Arabian (SA)-MB cases are sparse. MBs can be sub-grouped according to methylation patterns from FPPE samples into Wingless (WNT-MB), Sonic Hedgehog (SHH-MB), Group 3 (G3), and Group 4 (G4) tumors. The WNT-MB and SHH-MB subgroups are characterized by gain-of function mutations that activate oncogenic cell signaling, whilst G3/G4 tumors show recurrent chromosomal alterations. Given that each subgroup has distinct clinical outcomes, the ability to subgroup SA-FPPE samples holds significant prognostic and therapeutic value. Here, we performed the first assessment of MB-DNA methylation patterns in an SA cohort using archival biopsy material (FPPE n = 49). Of the 41 materials available for methylation assessments, 39 could be classified into the major DNA methylation subgroups (SHH, WNT, G3, and G4). Furthermore, methylation analysis was able to reclassify tumors that could not be sub-grouped through next-generation sequencing, highlighting its superior accuracy for MB molecular classifications. Independent assessments demonstrated known clinical relationships of the subgroups, exemplified by the high survival rates observed for WNT tumors. Surprisingly, the G4 subgroup did not conform to previously identified phenotypes, with a high prevalence in females, high metastatic rates, and a large number of tumor-associated deaths. Taking our results together, we demonstrate that DNA methylation profiling enables the robust sub-classification of four disease sub-groups in archival FFPE biopsy material from SA-MB patients. Moreover, we Alharbi et al. Clincal Methylation Profiling of Medulloblastomashow that the incorporation of DNA methylation biomarkers can significantly improve current disease-risk stratification schemes, particularly concerning the identification of aggressive G4 tumors. These findings have important implications for future clinical disease management in MB cases across the Arab world.

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