Molecular signatures define two main classes of meningiomas

Lucia Helena Carvalho,Peter Jun,Zora Modrusan,Scott R Vandenberg,Joseph F Costello,Gilson S Baia,Anita Lal,Ivan Smirnov,Michael W Mcdermott,Justin S Smith

doi:10.1186/1476-4598-6-64

Abstract

BackgroundMeningiomas are common brain tumors that are classified into three World Health Organization grades (benign, atypical and malignant) and are molecularly ill-defined tumors. The purpose of this study was identify molecular signatures unique to the different grades of meningiomas and to unravel underlying molecular mechanisms driving meningioma tumorigenesis.ResultsWe have used a combination of gene expression microarrays and array comparative genomic hybridization (aCGH) to show that meningiomas of all three grades fall into two main molecular groups designated 'low-proliferative' and 'high-proliferative' meningiomas. While all benign meningiomas fall into the low-proliferative group and all malignant meningiomas fall into the high-proliferative group, atypical meningiomas distribute into either one of these groups. High-proliferative atypical meningiomas had an elevated median MIB-1 labeling index and a greater frequency of copy number aberrations (CNAs) compared to low-proliferative atypical meningiomas. Additionally, losses on chromosome 6q, 9p, 13 and 14 were found exclusively in the high-proliferative meningiomas. We have identified genes that distinguish benign low-proliferative meningiomas from malignant high-proliferative meningiomas and have found that gain of cell-proliferation markers and loss of components of the transforming growth factor-beta signaling pathway were the major molecular mechanisms that distinguish these two groups.ConclusionCollectively, our data suggests that atypical meningiomas are not a molecularly distinct group but are similar to either benign or malignant meningiomas. It is anticipated that identified molecular and CNA markers will potentially be more accurate prognostic markers of meningiomas.

Highlights

Meningiomas are common brain tumors that are classified into three World Health Organization grades and are molecularly ill-defined tumors
We performed pairwise comparisons between the three WHO grades of meningiomas using Significance Analysis of Microarrays (SAM) analysis. 28 genes were differentially expressed between Grade 1 and 2 meningiomas and no genes were differentially expressed between Grade 2 and Grade 3 meningiomas using a criterion of q < 0.05 and fold > 2
Since SAM analysis utilizes the median expression of individual genes within each group to calculate fold changes, this result suggests that Grade 2 meningiomas were the most heterogeneous group with expression profiles of individual tumors matching both Grade 1 and Grade 3 meningiomas

Summary

Introduction

Meningiomas are common brain tumors that are classified into three World Health Organization grades (benign, atypical and malignant) and are molecularly ill-defined tumors. Meningiomas account for ~30% of all primary central nervous system tumors [1] These tumors are classified into three WHO Grades based on histopathological criteria. While benign meningioma patients can often be cured by surgical resection alone, atypical and malignant meningioma patients have worse clinical outcomes [4]. While local 5-year recurrence rates are 5% for benign meningiomas, they are about 40% for totally resected atypical meningiomas. There remains considerable variability in clinical outcomes within each grade, especially among atypical meningiomas. A molecular based classification system has the likelihood of being a better prognostic indicator and is useful for identifying alterations in pathways and networks that drive tumor progression and growth [8]. The information obtained can potentially be translated into more effective and less toxic targeted therapies [8]

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