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Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors.

ABSTRACT: BACKGROUND: Tumor transcriptomes contain information of critical value to understanding the different capacities of a cell at both a physiological and pathological level. In terms of clinical relevance, they provide information regarding the cellular "toolbox" e.g., pathways associated with malignancy and metastasis or drug dependency. Exploration of this resource can therefore be leveraged as a translational tool to better manage and assess neoplastic behavior. The availability of public genome-wide expression datasets, provide an opportunity to reassess neuroendocrine tumors at a more fundamental level. We hypothesized that stringent analysis of expression profiles as well as regulatory networks of the neoplastic cell would provide novel information that facilitates further delineation of the genomic basis of small intestinal neuroendocrine tumors. RESULTS: We re-analyzed two publically available small intestinal tumor transcriptomes using stringent quality control parameters and network-based approaches and validated expression of core secretory regulatory elements e.g., CPE, PCSK1, secretogranins, including genes involved in depolarization e.g., SCN3A, as well as transcription factors associated with neurodevelopment (NKX2-2, NeuroD1, INSM1) and glucose homeostasis (APLP1). The candidate metastasis-associated transcription factor, ST18, was highly expressed (>14-fold, p < 0.004). Genes previously associated with neoplasia, CEBPA and SDHD, were decreased in expression (-1.5 - -2, p < 0.02). Genomic interrogation indicated that intestinal tumors may consist of two different subtypes, serotonin-producing neoplasms and serotonin/substance P/tachykinin lesions. QPCR validation in an independent dataset (n = 13 neuroendocrine tumors), confirmed up-regulated expression of 87% of genes (13/15). CONCLUSIONS: An integrated cellular transcriptomic analysis of small intestinal neuroendocrine tumors identified that they are regulated at a developmental level, have key activation of hypoxic pathways (a known regulator of malignant stem cell phenotypes) as well as activation of genes involved in apoptosis and proliferation. Further refinement of these analyses by RNAseq studies of large-scale databases will enable definition of individual master regulators and facilitate the development of novel tissue and blood-based tools to better understand diagnose and treat tumors.

SUBMITTER: Kidd M

PROVIDER: S-EPMC4124138 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors.

Kidd Mark M Modlin Irvin M IM Drozdov Ignat I

BMC genomics 20140715

<h4>Background</h4>Tumor transcriptomes contain information of critical value to understanding the different capacities of a cell at both a physiological and pathological level. In terms of clinical relevance, they provide information regarding the cellular "toolbox" e.g., pathways associated with malignancy and metastasis or drug dependency. Exploration of this resource can therefore be leveraged as a translational tool to better manage and assess neoplastic behavior. The availability of public ...[more]

PMID: 25023465

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Project description:BackgroundPatients with small intestinal neuroendocrine tumors (SINETs) frequently present with lymph node and liver metastases at the time of diagnosis, but the molecular changes that lead to the progression of these tumors are largely unknown. Sequencing studies have only identified recurrent point mutations at low frequencies with CDKN1B being the most common harboring heterozygous mutations in less than 10% of all tumors. Although SINETs are genetically stable tumors with a low frequency of point mutations and indels, they often harbor recurrent hemizygous copy number alterations (CNAs) yet the functional implications of these CNA are unclear.MethodsUtilizing comparative genomic hybridization (CGH) arrays we analyzed the CNA profile of 131 SINETs from 117 patients. Two tumor suppressor genes and corresponding proteins i.e. SMAD4, and CDKN1B, were further characterized using a tissue microarray (TMA) with 846 SINETs. Immunohistochemistry (IHC) was used to quantify protein expression in TMA samples and this was correlated with chromosome number evaluated with fluorescent in-situ hybridization (FISH). Intestinal tissue from a Smad4+/- mouse model was used to detect entero-endocrine cell hyperplasia with IHC.ResultsAnalyzing the CGH arrays we found loss of chromosome 18q and SMAD4 in 71% of SINETs and that focal loss of chromosome 12 affecting the CDKN1B was present in 9.4% of SINETs. No homozygous loss of chromosome 18 was detected. Hemizygous loss of SMAD4, but not CDKN1B, significantly correlated with reduced protein levels but hemizygous loss of SMAD4 did not induce entero-endocrine cell hyperplasia in the Smad4+/- mouse model. In addition, patients with low SMAD4 protein expression in primary tumors more often presented with metastatic disease.ConclusionsHemizygous loss of chromosome 18q and the SMAD4 gene is the most common genetic event in SINETs and our results suggests that this could influence SMAD4 protein expression and spread of metastases. Although SMAD4 haploinsufficiency alone did not induce tumor initiation, loss of chromosome 18 could represent an evolutionary advantage in SINETs explaining the high prevalence of this aberration. Functional consequences of reduced SMAD4 protein levels could hypothetically be a potential mechanism as to why loss of chromosome 18 appears to be clonally selected in SINETs.

Project description:Background: Small intestinal neuroendocrine tumors (SI-NETs) are the most common malignant tumors of the small intestine, with many patients presenting with metastases and their incidence increasing. We aimed to find effective diagnostic biomarkers for patients with primary and metastatic SI-NETs that could be applied for clinical diagnosis. Methods: We downloaded GSE65286 (training set) and GSE98894 (test set) from the GEO database and performed differential gene expression analysis to obtain differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DElncRNAs). The functions and pathways involved in these genes were further explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. In addition, a global regulatory network involving dysregulated genes in SI-NETs was constructed based on RNAInter and TRRUST v2 databases, and the diagnostic power of hub genes was identified by receiver operating characteristic curve (ROC). Results: A total of 2,969 DEGs and DElncRNAs were obtained in the training set. Enrichment analysis revealed that biological processes (BPs) and KEGG pathways were mainly associated with cancer. Based on gene set enrichment analysis (GSEA), we obtained five BPs (cytokinesis, iron ion homeostasis, mucopolysaccharide metabolic process, platelet degranulation and triglyceride metabolic process) and one KEGG pathway (ppar signaling pathway). In addition, the core set of dysregulated genes obtained included MYL9, ITGV8, FGF2, FZD7, and FLNC. The hub genes were upregulated in patients with primary SI-NETs compared to patients with metastatic SI-NETs, which is consistent with the training set. Significantly, the results of ROC analysis showed that the diagnostic power of the hub genes was strong in both the training and test sets. Conclusion: In summary, we constructed a global regulatory network in SI-NETs. In addition, we obtained the hub genes including MYL9, ITGV8, FGF2, FZD7, and FLNC, which may be useful for the diagnosis of patients with primary and metastatic SI-NETs.

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Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors.

Publications

Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors.

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