Specific gene expression signatures of low grade meningiomas

Abstract

IntroductionMeningiomas are the most common primary central nervous system (CNS) tumors in adults, representing approximately one-third of all primary adult CNS tumors. Although several recent publications have proposed alternative grading systems of meningiomas that incorporate genomic and/or epigenomic data to better predict meningioma recurrence and progression-free survival, our understanding of driving forces of meningioma development is still limited.ObjectiveTo define gene expression signatures of the most common subtypes of meningiomas to better understand cellular processes and signaling pathways specific for each tumor genotype.MethodsWe used RNA sequencing (RNA-seq) to determine whole transcriptome profiles of twenty meningiomas with genomic alterations including NF2 inactivation, loss of chr1p, and missense mutations in TRAF7, AKT1 and KLF4.ResultsThe analysis revealed that meningiomas with NF2 gene inactivation expressed higher levels of BCL2 and GLI1 compared with tumors harboring TRAF7 missense mutations. Moreover, NF2 meningiomas were subdivided into two distinct groups based on additional loss of chr1p. NF2 tumors with intact chr1p were characterized by the high expression of tumor suppressor PTCH2 compared to NF2 tumors with chr1p loss. Taken together with the high expression of BCL2 and GLI1, these results suggest that activation of Sonic Hedgehog pathway may contribute to NF2 meningioma development. In contrast, NF2 tumors with chr1p loss expressed high levels of transcription factor FOXD3 and its antisense RNA FOXD3-AS1. Examination of TRAF7 tumors demonstrated that TRAF7 regulates a number of biomechanically responsive genes (KRT6a, KRT16, IL1RL1, and AQP3 among others). Interestingly, AKT1 and KLF4 meningiomas expressed genes specific for PI3K/AKT signaling pathway, suggesting overlapping gene signatures between the two subtypes. In addition, KLF4 meningiomas had high expression of carcinoembryonic antigen family members CEACAM6 and CEACAM5.ConclusionsEach group of meningiomas displayed a unique gene expression signature suggesting signaling pathways potentially implicated in tumorigenesis. These findings will improve our understanding of meningioma tumorigenesis and prognosis.

Unveiling a Biomarker Signature of Meningioma: The Need for a Panel of Genomic, Epigenetic, Proteomic, and RNA Biomarkers to Advance Diagnosis and Prognosis

“…Recent developments in genomics have led to further stratification of meningioma subtypes based on alterations in somatic gene copy numbers and genome-wide profiling of DNA methylation [20,40,41]. Patel et al combined whole-genome sequencing and transcriptome analysis and suggested the classification of meningiomas into three major types: type A includes missense mutations in TRAF7, KLF4, and AKT1 and has minimal chromosomal alterations [42], similar to previous findings in benign meningiomas [40]; type B includes NF2-deficient non-aggressive meningiomas; and type C includes more aggressive meningiomas, which have a significant chromosomal instability and chromosomal gains and losses, most commonly losses of both chr22q and chr1p [42]. Using these molecular principles, Tsitsikov et al compared transcriptional profiles of four of the most common benign types of meningiomas: (1) NF2 loss versus meningiomas with TRAF7 missense mutations, (2) NF2 tumors with or without additional loss of chr1p, and (3) TRAF7 meningiomas with additional missense mutations in AKT1 or KLF4.…”

“…Using these molecular principles, Tsitsikov et al compared transcriptional profiles of four of the most common benign types of meningiomas: (1) NF2 loss versus meningiomas with TRAF7 missense mutations, (2) NF2 tumors with or without additional loss of chr1p, and (3) TRAF7 meningiomas with additional missense mutations in AKT1 or KLF4. Their analysis showed distinct transcriptional programs specific for each meningioma genotype [40]. Other studies have integrated multiple parameters, including DNA methylation, RNA-seq, and cytogenetic profiling to enhance the grading of meningiomas [43,44].…”

Unveiling a Biomarker Signature of Meningioma: the Need for a Panel of Genomic, Epigenetic, Proteomic, and RNA Biomarkers to Advance Diagnosis and Prognosis

“…Recent developments in genomics have led to further stratification of meningioma subtypes based on alterations in somatic gene copy numbers and genome-wide profiling of DNA methylation [20,39,40]. Patel et al combined whole genome sequencing and transcriptome analysis and suggested another classification of meningiomas into 3 major types: type A have missense mutations in TRAF7, KLF4, and AKT1 and have minimal chromosomal alterations [41], similar to previous findings in benign meningiomas [39]; type B are NF2-deficient non-aggressive meningiomas; and type C are more aggressive meningiomas which have a significant chromosomal instability and chromosomal gains and losses, most commonly loss of both chr22q and chr1p [41]. Using these molecular principles, Tsitsikov et al compared transcriptional profiles of four of the most common benign types of meningiomas: 1) NF2 loss versus meningiomas with TRAF7 missense mutations, 2) NF2 tumors with or without additional loss of chr1p, 3).…”

“…TRAF7 meningiomas with additional missense mutations in AKT1 or KLF4. Their analysis showed distinct transcriptional programs specific for each meningioma genotype [39]. Other studies have integrated multiple parameters, including DNA methylation, RNA-seq, and cytogenetic profiling to enhance the grading of meningiomas [42,43].…”