A CTNNB1-altered medulloblastoma shows the immunophenotypic, DNA methylation and transcriptomic profiles of SHH-activated, and not WNT-activated, medulloblastoma.

Recent advancements in molecular characterisation have identified four principal molecular groups of medulloblastoma: WNT, SHH, group 3 and group 4. Each has its characteristic clinical features, signature genetic alterations and distinct DNA methylome profiles. Thus far, CTNNB1 mutations have been considered pathognomonic of WNT-activated medulloblastoma. Furthermore, it has been shown that CTNNB1 mutations dominantly drive the WNT-activated phenotype in medulloblastoma, even in the presence of alterations in the SHH pathway. We herein report an illustrative case that challenges this belief-a medulloblastoma with a pathogenic CTNNB1 mutation that otherwise showed the histopathology, immunophenotype and methylation and transcriptomic profiles of an SHH-activated medulloblastoma. Detailed molecular analyses, including whole exome sequencing, transcriptome analysis and DNA methylation profiling with DKFZ brain tumour classifier and St. Jude MLPnet neural network classifier analyses, have been performed on the tumour. Our example emphasises the diagnostic value of the immunohistochemistry panel with YAP1, GAB1 and ß-catenin and DNA methylation profiling, combined with exome sequencing, in the characterisation of medulloblastoma. CTNNB1 mutations are not specific for WNT-activated medulloblastoma, and different CTNNB1 mutations have diverse oncogenic potential.

Prognostic impact of tumor location and gene expression profile in sporadic desmoid tumor.

PURPOSE: Prognostic biomarkers remain necessary in sporadic desmoid tumor (DT) because the clinical course is unpredictable. DT location along with gene expression between thoracic and abdominal wall locations was analyzed. METHOD: Sporadic DT patients (GEIS Registry) diagnosed between 1982 and 2018 who underwent upfront surgery were enrolled retrospectively in this study. The primary endpoint was relapse-free survival (RFS). Additionally, the gene expression profile was analyzed in DT localized in the thoracic or abdominal wall, harboring the most frequent CTNNB1 T41A mutation. RESULTS: From a total of 454 DT patients, 197 patients with sporadic DT were selected. The median age was 38.2 years (1.8-89.1) with a male/female distribution of 33.5/66.5. Most of them harbored the CTNNB1 T41A mutation (71.6 %), followed by S45F (17.8 %) and S45P (4.1 %). A significant worse median RFS was associated with males (p = 0.019), tumor size ≥ 6 cm (p = 0.001), extra-abdominal DT location (p < 0.001) and the presence of CTNNB1 S45F mutation (p = 0.013). In the multivariate analysis, extra-abdominal DT location, CTNNB1 S45F mutation and tumor size were independent prognostic biomarkers for worse RFS. DTs harboring the CTNNB1 T41A mutation showed overexpression of DUSP1, SOCS1, EGR1, FOS, LIF, MYC, SGK1, SLC2A3, and IER3, and underexpression of BMP4, PMS2, HOXA9, and WISP1 in thoracic versus abdominal wall locations. CONCLUSION: Sporadic DT location exhibits a different prognosis in terms of RFS favoring the abdominal wall compared to extra-abdominal sites. A differential gene expression profile under the same CTNNB1 T41A mutation is observed in the abdominal wall versus the thoracic wall, mainly affecting the Wnt/ß-catenin, TGFß, IFN, and TNF pathways.