Loss of 5 '-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness

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de Menezes, Weder Pereira ; Oliveira Silva, Viviane Aline ; Faria Gomes, Izabela Natalia ; Rosa, Marcela Nunes ; Corcoll Spina, Maria Luisa ; Carloni, Adriana Cruvinel ; Vieira Alves, Ana Laura ; Melendez, Matias ; Almeida, Gisele Caravina ; da Silva, Luciane Sussuchi ; Clara, Carlos ; da Cunha, Isabela Werneck ; Maroso Hajj, Glaucia Noeli ; Jones, Chris ; Bidinotto, Lucas Tadeu ; Reis, Rui Manuel

• Document type: Journal article
• Source: CELLS; v. 9, n. 2, p. 24-pg., 2020-02-01.

Abstract

The 5'-methylthioadenosine phosphorylase (MTAP) gene is located in the chromosomal region 9p21. MTAP deletion is a frequent event in a wide variety of human cancers; however, its biological role in tumorigenesis remains unclear. The purpose of this study was to characterize the MTAP expression profile in a series of gliomas and to associate it with patients' clinicopathological features. Moreover, we sought to evaluate, through glioma gene-edited cell lines, the biological impact of MTAP in gliomas. MTAP expression was evaluated in 507 glioma patients by immunohistochemistry (IHC), and the expression levels were associated with patients' clinicopathological features. Furthermore, an in silico study was undertaken using genomic databases totalizing 350 samples. In glioma cell lines, MTAP was edited, and following MTAP overexpression and knockout (KO), a transcriptome analysis was performed by NanoString Pan-Cancer Pathways panel. Moreover, MTAP's role in glioma cell proliferation, migration, and invasion was evaluated. Homozygous deletion of 9p21 locus was associated with a reduction of MTAP mRNA expression in the TCGA (The Cancer Genome Atlas) - glioblastoma dataset (p < 0.01). In addition, the loss of MTAP expression was markedly high in high-grade gliomas (46.6% of cases) determined by IHC and Western blotting (40% of evaluated cell lines). Reduced MTAP expression was associated with a better prognostic in the adult glioblastoma dataset (p < 0.001). Nine genes associated with five pathways were differentially expressed in MTAP-knockout (KO) cells, with six upregulated and three downregulated in MTAP. Analysis of cell proliferation, migration, and invasion did not show any significant differences between MTAP gene-edited and control cells. Our results integrating data from patients as well as in silico and in vitro models provide evidence towards the lack of strong biological importance of MTAP in gliomas. Despite the frequent loss of MTAP, it seems not to have a clinical impact in survival and does not act as a canonic tumor suppressor gene in gliomas. (AU)

• FAPESP's process: 16/18907-0 - Characterization of the involvement of WNK2 protein in autophagic and endocytic vesicle traffic in glioma
• Grantee: Ana Laura Vieira Alves
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 16/06833-2 - Molecular characterization of MTAP (Methylthioadenosine phosphorylase) and evaluation of therapeutic potential in gliomas
• Grantee: Weder Pereira de Menezes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/22305-9 - Study of biomarkers of cetuximab response and perspective of application of anti-EGFR combi-molecules in solid tumors
• Grantee: Izabela Natalia Faria Gomes
• Support Opportunities: Scholarships in Brazil - Doctorate