Dataset Information

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma.

ABSTRACT: BACKGROUND:Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes. METHODS:The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways. RESULTS:There were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 (MMP1, ANLN, CEP55, and TFPI2) are known to play a role in ATC progression; however, 6/10 genes (TMEM158, CXCL5, E2F7, DLGAP5, MME, and ASPM) had not been specifically implicated in ATC. Similarly, 3/10 (SFTA3, LMO3, and C2orf40) of the most globally downregulated genes were novel in this context, while 7/10 genes (SLC26A7, TG, TSHR, DUOX2, CDH1, PDE8B, and FOXE1) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors (KLF16, SP3, ETV6, FOXC1, SP1, EGFR1, and MAFK) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that "mitotic cell cycle" is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p-value <10-30). CONCLUSIONS:By focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.

SUBMITTER: Weinberger P

PROVIDER: S-EPMC5314727 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma.

Weinberger Paul P Ponny Sithara Raju SR Xu Hongyan H Bai Shan S Smallridge Robert R Copland John J Sharma Ashok A

Thyroid : official journal of the American Thyroid Association 20161215 2

<h4>Background</h4>Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes.<h4>Methods</h4>The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughpu ...[more]

PMID: 27796151

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Project description:Background Since anaplastic thyroid carcinoma (ATC) has rapid progression and a poor outcome, identification of the key genes and underlying mechanisms of ATC is required. Methods Gene expression profiles of GSE29265 and GSE33630 were available from the Gene Expression Omnibus database. The two profile datasets included 19 ATC tissues, 55 normal thyroid tissues and 59 papillary thyroid cancer (PTC) tissues. Differentially expressed genes (DEGs) between ATC tissues and normal thyroid tissues as well as ATC tissues and PTC tissues were identified using the GEO2R tool. Common DEGs between the two datasets were selected via Venn software online. Then, we applied the Database for Annotation, Visualization and Integrated Discovery for Kyoto Encyclopedia of Gene and Genome pathway and gene ontology (GO) analyses. Additionally, protein-protein interactions (PPIs) of these DEGs were visualized via Cytoscape with Search Tool for the Retrieval of Interacting Genes. In the PPI networks analyzed by the Molecular Complex Detection plug-in, all 54 upregulated core genes were selected. Furthermore, Kaplan-Meier analysis was applied to analyze overall survival based on these 54 genes. Then, we used the DrugBank database to identify drug relationships for the 54 genes. Additionally, we validated the correlations between genes enriched in pathways and genes identified as prognosis biomarkers of THCA by Gene Expression Profiling Interactive Analysis. Results Four genes (CCNB1, CCNB2, CDK1 and CHEK1) involved cell cycle arrest and DNA repair were significantly enriched in the G2/M phase of the cell cycle pathway and before G2 phase arrest of the P53 pathway. Inhibitors of CHEK1, CDK1 and TOP2A were identified in the DrugBank database. ANLN, DEPDC1, KIF2C, CENPN, TACC3 CCNB2 and CDC6 were hypothesized to be prognostic biomarkers of ATC. Furthermore, CCNB1, CCNB2, CDK1 and CHEK1 were significantly positively associated with these prognosis genes. Conclusions CCNB1, CCNB2, CDK1 and CHEK1 may be key genes involved cell cycle arrest and DNA damage repair in ATC. Further studies are required to confirm the contributions of the identified genes to ATC progression and survival.

Project description:Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and it is less than 2% of thyroid carcinomas (TCs). The standard treatment of ATC includes surgical debulking, accelerated hyperfractionated external beam radiation therapy (EBRT), and chemotherapy, in particular with cisplatin or doxorubicin, achieving about 10 months of median survival. Since ATC is a rare and aggressive tumor, it is still challenging to predict the patient clinical therapy responsiveness. Several genetic mutations have been described in ATC, involved in different molecular pathways linked to tumor progression, and novel therapies acting on these molecular pathways have been investigated, to improve the quality of life in these patients. Here we review the new targeted therapy of ATC. We report interesting results obtained with molecules targeting different pathways: angiogenesis (vandetanib, combretastatin, sorafenib, lenvatinib, sunitinib, CLM94, CLM3, etc.); EGFR (gefitinib, docetaxel); BRAF (dabrafenib/trametinib, vemurafenib); PPARγ agonists (rosiglitazone, pioglitazone, efatutazone); PD-1 and PD-L1 (pembrolizumab); TERT. To escape resistance to monotherapies, the evaluation of combination strategies with radiotherapy, chemotherapy, or targeted drugs is ongoing. The results of clinical trials with dabrafenib and trametinib led to the approval from FDA of this combination for patients with BRAF V600E mutated ATC with locally advanced, unresectable, or metastatic ATC. The anti-PD-L1 antibody immunotherapy, alone or combined with a BRAF inhibitor, has been shown also promising in the treatment of ATC. Furthermore, to increase the therapeutic success and not to use ineffective or even harmful treatments, a real tailored therapy should be pursued, and this can be achieved thanks to the new available genomic analysis methods and to the possibility to test in vitro novel treatments directly in primary cells from each ATC patient. Exploring new treatment strategies is mandatory to improve the survival of these patients, guaranteeing a good quality of life.

Dataset Information

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma.

Publications

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma.

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