Abstract
Meningiomas are the most common primary brain tumor of adults. The majority are benign (WHO grade I), with a mostly indolent course; 20% of them (WHO grade II and III) are, however, considered aggressive and require a more complex management. WHO grade II and III tumors are heterogeneous and, in some cases, can develop from a prior lower grade meningioma, although most arise de novo. Mechanisms leading to progression or implicated in de novo grade II and III tumorigenesis are poorly understood. RNA-seq was used to profile the transcriptome of grade I, II, and III meningiomas and to identify genes that may be involved in progression. Bioinformatic analyses showed that grade I meningiomas that progress to a higher grade are molecularly different from those that do not. As such, we identify GREM2, a regulator of the BMP pathway, and the snoRNAs SNORA46 and SNORA48, as being significantly reduced in meningioma progression. Additionally, our study has identified several novel fusion transcripts that are differentially present in meningiomas, with grade I tumors that did not progress presenting more fusion transcripts than all other tumors. Interestingly, our study also points to a difference in the tumor immune microenvironment that correlates with histopathological grade.
Highlights
Meningiomas, neoplasms of mesodermal-arachnoid origin, are the most common primary intracranial and spinal tumor [18]
We identify GREMLIN 2 (GREM2), a regulator of the BMP pathway [3], and the small nucleolar RNAs SNORA46 and SNORA48 as novel, previously uncharacterized, downregulated candidate genes that may be linked to meningioma progression
Transcriptional profile across different meningioma WHO grades The discovery set chosen for RNA-seq (Table 1) consisted of 25 meningioma samples from 20 patients, which included: samples from grade I tumors that did not progress to higher grade, samples from de novo grade II or III tumors, samples from patients with tumors which progressed from grade I to grade II and samples from a patient with a tumor progressing from grade II to III
Summary
Meningiomas, neoplasms of mesodermal-arachnoid origin, are the most common primary intracranial and spinal tumor [18]. About 80% show benign behavior and are amenable to surgical resection alone. 20% can clinically recur and require multimodal treatment (repeat surgery and radiotherapy). Histopathological grade is the main predictor of meningioma behavior, with most WHO grade I (called ‘benign’) tumors having a nonmalignant course; on the other hand, grade II (‘atypical’) and III (‘anaplastic’) meningiomas are often more aggressive and recur [18]. The current WHO classification relies on histomorphological features to sub-classify meningiomas into 15 subtypes, nine for grade I and three each for grades. The major predictors for meningioma recurrence are WHO grade (with higher grades carrying a higher risk) and extent of surgical resection [7]. To complement and improve an all histology-based classification, new genomics-based approaches are emerging [33, 39, 43,44,45]
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