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Impact of a cell cycle and an extracellular matrix remodeling transcriptional signature on tumor progression and correlation with EZH2 expression in meningioma

Benedito Jamilson Araújo Pereira, Antonio Marcondes Lerario, Paula Rodrigues Sola, Talita de Sousa Laurentino, Dipika R. Mohan, Antonio Nogueira de Almeida, Paulo Henrique Pires de Aguiar, Wellingson da Silva Paiva, Alda Wakamatsu, Manoel Jacobsen Teixeira, Sueli Mieko Oba-Shinjo, and Suely Kazue Nagahashi Marie

OBJECTIVE

The authors searched for genetic and transcriptional signatures associated with tumor progression and recurrence in their cohort of patients with meningiomas, combining the analysis of targeted exome, NF2-LOH, transcriptome, and protein expressions.

METHODS

The authors included 91 patients who underwent resection of intracranial meningioma at their institution between June 2000 and November 2007. The search of somatic mutations was performed by Next Generation Sequencing through a customized panel and multiplex ligation-dependent probe amplification for NF2 loss of heterozygosity. The transcriptomic profile was analyzed by QuantSeq 3′ mRNA-Seq. The differentially expressed genes of interest were validated at the protein level analysis by immunohistochemistry.

RESULTS

The transcriptomic analysis identified an upregulated set of genes related to metabolism and cell cycle and downregulated genes related to immune response and extracellular matrix remodeling in grade 2 (atypical) meningiomas, with a significant difference in recurrent compared with nonrecurrent cases. EZH2 nuclear positivity associated with grade 2, particularly with recurrent tumors and EZH2 gene expression level, correlated positively with the expression of genes related to cell cycle and negatively to genes related to immune response and regulation of cell motility.

CONCLUSIONS

The authors identified modules of dysregulated genes in grade 2 meningiomas related to the activation of oxidative metabolism, cell division, cell motility due to extracellular remodeling, and immune evasion that were predictive of survival and exhibited significant correlations with EZH2 expression.