Identification of novel fusion transcripts in meningioma
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LABORATORY INVESTIGATION
Identification of novel fusion transcripts in meningioma A. Basit Khan1 · Ron Gadot1 · Arya Shetty1 · James C. Bayley V1 · Caroline C. Hadley1 · Maria F. Cardenas2 · Ali Jalali1 · Akdes S. Harmanci3 · Arif O. Harmanci3 · David A. Wheeler2 · Tiemo J. Klisch4,5 · Akash J. Patel1,4,6 Received: 30 May 2020 / Accepted: 8 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Introduction Meningiomas are the most common primary intracranial tumor. Recent next generation sequencing analyses have elaborated the molecular drivers of this disease. We aimed to identify and characterize novel fusion genes in meningiomas. Methods We performed a secondary analysis of our RNA sequencing data of 145 primary meningioma from 140 patients to detect fusion genes. Semi-quantitative rt-PCR was performed to confirm transcription of the fusion genes in the original tumors. Whole exome sequencing was performed to identify copy number variations within each tumor sample. Comparative RNA seq analysis was performed to assess the clonality of the fusion constructs within the tumor. Results We detected six fusion events (NOTCH3-SETBP1, NF2-SPATA13, SLC6A3-AGBL3, PHF19-FOXP2 in two patients, and ITPK1-FBP2) in five out of 145 tumor samples. All but one event (NF2-SPATA13) led to extremely short reading frames, making these events de facto null alleles. Three of the five patients had a history of childhood radiation. Four out of six fusion events were detected in expression type C tumors, which represent the most aggressive meningioma. We validated the presence of the RNA transcripts in the tumor tissue by semi-quantitative RT PCR. All but the two PHF19-FOXP2 fusions demonstrated high degrees of clonality. Conclusions Fusion genes occur infrequently in meningiomas and are more likely to be found in tumors with greater degree of genomic instability (expression type C) or in patients with history of cranial irradiation. Keywords Meningioma · Fusion gene · NF2 · RNA sequencing Tiemo J. Klisch and Akash J. Patel have contributed equally to this work.
Introduction
* Tiemo J. Klisch [email protected]
Meningiomas are the most common primary intracranial tumor, accounting for nearly one-third of all CNS tumors [1, 2]. While most are benign and effectively treated by surgery or radiosurgery, approximately 20% behave aggressively [3, 4]. Currently the World Health Organization (WHO) classifies these tumors as benign (grade I), atypical (grade II), and malignant (grade III) [5]. Next-generation sequencing (NGS) techniques have delineated the molecular underpinnings of meningiomas and helped differentiate benign from aggressive disease [6]. These studies have identified large scale copy number variations, recurrent mutations, methylation changes, and transcriptional changes involved in meningioma biology [7–9]. Biallelic NF2 loss, which can occur via chromosome 22q (chr22q) loss, inactivating NF2 mutation, or NF2 promotor methylation, is important in both benign and aggressive meningiomas [6
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