A Basit Khan1, Ron Gadot1, Arya Shetty1, James C Bayley1, Caroline C Hadley1, Maria F Cardenas2, Ali Jalali1, Akdes S Harmanci3, Arif O Harmanci3, David A Wheeler2, Tiemo J Klisch4,5, Akash J Patel6,7,8. 1. Department of Neurosurgery, Baylor College of Medicine, 7200 Cambridge 9th Floor, Houston, TX, 77030, USA. 2. Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA. 3. School of Biomedical Informatics, Center for Computational Systems Medicine, University of Texas Health Science Center At Houston, Houston, TX, 77030, USA. 4. Texas Children's Hospital, Jan and Dan Duncan Neurological Research Institute, Houston, TX, 77030, USA. klisch@bcm.edu. 5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. klisch@bcm.edu. 6. Department of Neurosurgery, Baylor College of Medicine, 7200 Cambridge 9th Floor, Houston, TX, 77030, USA. akash.patel@bcm.edu. 7. Texas Children's Hospital, Jan and Dan Duncan Neurological Research Institute, Houston, TX, 77030, USA. akash.patel@bcm.edu. 8. Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA. akash.patel@bcm.edu.
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.
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.
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