Dataset Information

Identification of key genes in invasive clinically non-functioning pituitary adenoma by integrating analysis of DNA methylation and mRNA expression profiles.

ABSTRACT:

Background

Tumor surrounding the internal carotid artery or invading to the cavernous sinus is an important characteristic of invasive pituitary adenoma, and a pivotal factor of tumor residue and regrowth. Without specific changes in serum hormone related to the adenohypophyseal cell of origin, clinically non-functioning pituitary adenoma is more likely to be diagnosed at invasive stages compared with functioning pituitary adenoma. The underlying mechanism of tumor invasion remains unknown. In this study, we aimed to identify key genes in tumor invasion by integrating analyses of DNA methylation and gene expression profiles.

Method

Genome-wide DNA methylation and mRNA microarray analysis were performed for tumor samples from 68 patients at the Beijing Tiantan Hospital. Differentially expressed genes and methylated probes were identified based on an invasive vs non-invasive grouping. Differentially methylated probes in the promoter region of targeted genes were assessed. Pearson correlation analysis was used to identify genes with a strong association between DNA methylation status and expression levels. Pyrosequencing and RT-PCR were used to validate the methylation status and expression levels of candidate genes, respectively.

Results

A total of 8842 differentially methylated probes, located on 4582 genes, and 661 differentially expressed genes were identified. Both promoter methylation and expression alterations were observed for 115 genes with 58 genes showing a negative correlation between DNA methylation status and expression level. Nineteen genes that exhibited notably negative correlations between DNA methylation and gene expression levels, are involved in various gene ontologies and pathways, or played an important role in different diseases, were regarded as candidate genes. We found an increased methylation with a decreased expression of PHYHD1, LTBR, C22orf42, PRR5, ANKDD1A, RAB13, CAMKV, KIFC3, WNT4 and STAT6, and a decreased methylation with an increased expression of MYBPHL. The methylation status and expression levels of these genes were validated by pyrosequencing and RT-PCR.

Conclusions

The DNA methylation and expression levels of PHYHD1, LTBR, MYBPHL, C22orf42, PRR5, ANKDD1A, RAB13, CAMKV, KIFC3, WNT4 and STAT6 are associated with tumor invasion, and these genes may become the potential genes for targeted therapy.

SUBMITTER: Cheng S

PROVIDER: S-EPMC6892283 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Identification of key genes in invasive clinically non-functioning pituitary adenoma by integrating analysis of DNA methylation and mRNA expression profiles.

Cheng Sen S Xie Weiyan W Miao Yazhou Y Guo Jing J Wang Jichao J Li Chuzhong C Zhang Yazhuo Y

Journal of translational medicine 20191203 1

<h4>Background</h4>Tumor surrounding the internal carotid artery or invading to the cavernous sinus is an important characteristic of invasive pituitary adenoma, and a pivotal factor of tumor residue and regrowth. Without specific changes in serum hormone related to the adenohypophyseal cell of origin, clinically non-functioning pituitary adenoma is more likely to be diagnosed at invasive stages compared with functioning pituitary adenoma. The underlying mechanism of tumor invasion remains unkno ...[more]

PMID: 31796052

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Project description:PurposeNon-functioning pituitary adenoma (NFPA) is a very common type of intracranial tumor, which can be locally invasive and can have a high recurrence rate. The tumor microenvironment (TME) shows a high correlation with tumor pathogenesis and prognosis. The current study aimed to identify microenvironment-related genes in NFPAs and assess their prognostic value.Methods73 NFPA tumor samples were collected from Beijing Tiantan Hospital and transcriptional expression profiles were obtained through microarray analysis. The immune and stromal scores of each sample were calculated through the ESTIMATE algorithm, and the patients were divided into high and low immune/stromal score groups. Intersection differentially expressed genes (DEGs) were then obtained to construct a protein-protein interaction (PPI) network. Potential functions and pathways of intersection DEGs were then analyzed through Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. The prognostic value of these genes was evaluated. The quantitative real-time polymerase chain reaction in another set of NFPA samples was used to confirm the credibility of the bioinformatics analysis.ResultsThe immune/stromal scores were significantly correlated with cavernous sinus (CS) invasion. The Kaplan-Meier curve indicated that the high immune score group was significantly related to poor recurrence-free survival. We identified 497 intersection DEGs based on the high vs. low immune/stromal score groups. Function enrichment analyses of 497 DEGs and hub genes from the PPI network showed that these genes are mainly involved in the immune/inflammatory response, T cell activation, and the phosphatidylinositol 3 kinase-protein kinase B signaling pathway. Among the intersection DEGs, 88 genes were further verified as significantly expressed between the CS invasive group and the non-invasive group, and five genes were highly associated with NFPA prognosis.ConclusionWe screened out a series of critical genes associated with the TME in NFPAs. These genes may play a fundamental role in the development and prognosis of NFPA and may yield new therapeutic targets.

Project description:Context : Non Functioning Pituitary Adenomas (NFPAs), although typically benign, may be locally invasive. Few datas are currently available related to the molecular process of invasion in sporadic pituitary adenomas. Markers of invasiveness, important for helping the clinician in the therapeutic strategy particularly in the decision for adjuvant radiotherapy, are currently lacking. Objective: Evaluate if invasive NFPAs display a specific expression profile compared with non invasive tumors. Methods: To address this issue, we selected 40 NFPAs (38 of the gonadotroph type) and classified them as invasive (n=22) or non invasive (n=18) on the basis of MRI and surgical findings. Then we performed pangenomic analysis based on Agilent Human Whole genome Gene Expression oligonucleotide microarray (44k) Expression in order to identify genes differentially expressed between invasive and non invasive NFPA. Experiements are made in dual color with tumor samples labelled in cyanine 5 and a pool of all tumors labelled in cyanine 3.The expressions of some genes identified by microarray screening were confirmed by real-time quantitative RT-PCR. The selection of genes was made on the basis of Ingenuity networks and degree of upregulation between invasive and non invasive tumors. Moreover, some genes of interest already described in the literature were added to the analysis. Results: Prediction class analysis showed that 346 genes discriminated between invasive and non invasive NFPAs (p<0.001); 233 were up- and 113 were down-regulated between the two groups. We then tested On the basis of Ingenuity networks and degree of upregulation between invasive and non invasive tumors, a set of eight genes, including MYO5A, IGFBP5, FLT3, NFE2L1, PTTG, MMP9, NCAM and NR1H3, was tested in quantitative PCR analysis and. Results confirmed those obtained in microarrays results.analysis. At the protein level, Myosin 5A (MYO5A) demonstrated stronger immunostaining in invasive NFPAs compared to non invasive NFPAs. Conclusions: We propose a molecular signature of eight genes of grossly invasive NFPAs as compared with non invasive tumors: The product of one of these genes, MYO5A, may be a useful marker of invasive process in tumoral specimens. The role of these genes in the invasiveness process and as prognostic markers of pituitary adenomas needs to be confirmedinvestigated. Method: Microarray analyses the transcriptome of 22 invasive Non Functional Pituitary Adenomas (NFPAs) and 18 non invasive NFPAs in dual color (each sample labelled in cyanine 5 and a pool of all tumors labelled in cyanine 3).

Dataset Information

Identification of key genes in invasive clinically non-functioning pituitary adenoma by integrating analysis of DNA methylation and mRNA expression profiles.

Background

Method

Results

Conclusions

Publications

Identification of key genes in invasive clinically non-functioning pituitary adenoma by integrating analysis of DNA methylation and mRNA expression profiles.

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