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. 2019 Jun 6:10:361.
doi: 10.3389/fendo.2019.00361. eCollection 2019.

Co-expression Network Analysis Elucidated a Core Module in Association With Prognosis of Non-functioning Non-invasive Human Pituitary Adenoma

Busra Aydin  1 , Kazim Yalcin Arga  1
Affiliations

Co-expression Network Analysis Elucidated a Core Module in Association With Prognosis of Non-functioning Non-invasive Human Pituitary Adenoma

Busra Aydin et al. Front Endocrinol (Lausanne). .

Abstract

Non-functioning pituitary adenomas (NFPAs) are tumors with clinically challenging features since they have insidious progression. A complex network of gene interactions is thought to have roles in tumor formation and progression. Therefore, revealing the genetic network behind NFPA tumorigenesis is not only essential to attain further knowledge of tumor biology, but also plays a fundamental role in the development of efficacious treatment strategies. Differential co-expression network analysis is an outstanding approach for elucidation of groups of genes which show distinct co-expression patterns among phenotypes. In this study, we carried out a differential co-expression network analysis of NFPA-associated transcriptome dataset (n = 40) considering invasive (n = 22) and non-invasive (n = 18) phenotypes. Furthermore, we identified differentially co-expressed and co-regulated mRNA modules, which might be considered as potential systems biomarkers for NFPA prognosis and invasiveness. As a result, we have identified a novel 13-gene module, including CEACAM6, CYP4B1, EIF2S2, HID1, IFFO1, MYO18A, PDCD2, SGIP1, SWSAP1, and four unknown genes (A_24_P127621, A_24_P255786, A_24_P683553, and A_24_P916979), which was able to categorize the patients into two groups as invasive and non-invasive NFPA with distinct prognosis. The prognostic core module genes were associated with progression and prognosis of brain and glandular based cancers as well. Furthermore, these module genes were also expressed in blood, salivary gland, and spinal cord tissues. These results may provide the evidence on featured gene module which might play a prominent role in NFPA prognosis and sub-typing as effective biomarkers and therapeutic targets in the future.

Keywords: biomarker; co-expression; differential co-expression network; invasiveness; non-functional pituitary adenoma; prognosis.

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Figures

Figure 1
Figure 1
The expression values of MKI67 gene, which encodes Ki-67 protein, between tumor groups.
Figure 2
Figure 2
Biological process and pathway enrichments of DEGs. (A) Biological process enrichments of up- and down-regulated DEGs. (B) Pathway enrichments of DEGs.
Figure 3
Figure 3
Differentially co-expressed gene networks of invasive and non-invasive states. (A) The co-expression network in invasive phenotype (ICON) with 183 links among 162 and topological features of ICON (B) the non-invasive co-expression network (NICON), which includes 2,385 links among 562 genes and topological features of the network (C) Functional annotations of ICON hub genes (D) Functional annotations of NICON hub genes.
Figure 4
Figure 4
Principle Components Analysis (PCA) plots of differentially co-expressed gene modules (M3, M6, M7, and core module) that have significant prognostic performance.
Figure 5
Figure 5
The degree of co-expression of core module genes between invasive and non-invasive states. Upper-triangle represents invasive state whereas lower-triangle shows non-invasive state.
Figure 6
Figure 6
Clustering of sub-types of NFPA with PCA analysis. (A) The clustering of samples via first principle component of expression profiles of core module genes (B) survival analysis by Cox regression model and Kaplan-Meier estimates indicated the predictive power of patient survival among the sub-types.
Figure 7
Figure 7
Transcriptional regulators of prognostic genes. (A) Transcription factors that regulate prognostic core module genes (B) microRNAs (miRNAs) regulating the core module genes.
Figure 8
Figure 8
Prognostic power of core module through related tissue type cancers. Core module was also prognostic for (A) Adrenocortical carcinoma, (B) breast adenocarcinoma, (C) ovarian serous adenocarcinoma.
Figure 9
Figure 9
Prognostic power of core module through 3 types of brain tumors. (A) glioblastoma, (B) meningioma, (C) medulloblastoma.
Figure 10
Figure 10
Tissue-specific expressions of core module genes.
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