Integrated molecular analysis of adult sonic hedgehog (SHH)-activated medulloblastomas reveals two clinically relevant tumor subsets with VEGFA as potent prognostic indicator.

Abstract

BACKGROUND:

Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology. Approximately 70% of adult MB disclose a sonic hedgehog (SHH) molecular signature in contrast to about 30% in pediatric cohorts. In addition, adult SHH-MB (aSHH-MB) are clinically heterogeneous but there is consensus neither on their optimal treatment nor on risk stratification. Thus, the identification of clinically relevant molecular subsets of aSHH-MB and identification of potential treatment targets remains inconclusive.

METHODS:

We analyzed 96 samples of institutionally diagnosed aSHH-MB through genome-wide DNA methylation profiling, targeted DNA sequencing, and RNA sequencing to identify molecular subcategories of these tumors and assess their prognostic significance.

RESULTS:

We defined two aSHH-MB numerically comparable epigenetic subsets with clinical and molecular variability. The subset "aSHH-MBI" (46%/48%) was associated with PTCH1/SMO (54%/46%) mutations, "neuronal" transcriptional signatures, and favorable outcomes after combined radio-chemotherapy (5-year PFS = 80% and OS = 92%). The clinically unfavorable "aSHH-MBII" subset (50%/52%; 5-year PFS = 24% and OS = 45%) disclosed GLI2 amplifications (8%), loss of 10q (22%), and gene expression signatures associated with angiogenesis and embryonal development. aSHH-MBII tumors revealed strong and ubiquitous expression of VEGFA both at transcript and protein levels that was correlated with unfavorable outcome.

CONCLUSIONS:

(1) The histologically uniform aSHH-MB cohort exhibits clear molecular heterogeneity separating these tumors into two molecular subsets (aSHH-MBI and aSHH-MBII), which are associated with different cytogenetics, mutational landscapes, gene expression signatures, and clinical course. (2) VEGFA appears to be a promising biomarker to predict clinical course, which needs further prospective validation as its potential role in the pathogenesis of this subset.

• Authors: Andrey Korshunov, Konstantin Okonechnikov, Damian Stichel, Marina Ryzhova, Daniel Schrimpf, Felix Sahm, Philipp Sievers, Oksana Absalyamova, Olga Zheludkova, Andrey Golanov, David T W Jones, Stefan M Pfister, Andreas von Deimling, Marcel Kool
• Journal: Neuro-oncology (Neuro Oncol) Vol. 23 Issue 9 Pg. 1576-1585 (09 01 2021) ISSN: 1523-5866 [Electronic] England
• PMID: 33589929 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Hedgehog Proteins
• SHH protein, human
• VEGFA protein, human
• Vascular Endothelial Growth Factor A

Topics

• Adult
• Cerebellar Neoplasms (genetics)
• Child
• Hedgehog Proteins (genetics)
• Humans
• Medulloblastoma (genetics)
• Prognosis
• Transcriptome
• Vascular Endothelial Growth Factor A