Dataset Information

Frequent amplification of CENPF, GMNN and CDK13 genes in hepatocellular carcinomas.

ABSTRACT: Genomic changes frequently occur in cancer cells during tumorigenesis from normal cells. Using the Illumina Human NS-12 single-nucleotide polymorphism (SNP) chip to screen for gene copy number changes in primary hepatocellular carcinomas (HCCs), we initially detected amplification of 35 genes from four genomic regions (1q21-41, 6p21.2-24.1, 7p13 and 8q13-23). By integrated screening of these genes for both DNA copy number and gene expression in HCC and colorectal cancer, we selected CENPF (centromere protein F/mitosin), GMNN (geminin, DNA replication inhibitor), CDK13 (cyclin-dependent kinase 13), and FAM82B (family with sequence similarity 82, member B) as common cancer genes. Each gene exhibited an amplification frequency of ~30% (range, 20-50%) in primary HCC (n = 57) and colorectal cancer (n = 12), as well as in a panel of human cancer cell lines (n = 70). Clonogenic and invasion assays of NIH3T3 cells transfected with each of the four amplified genes showed that CENPF, GMNN, and CDK13 were highly oncogenic whereas FAM82B was not. Interestingly, the oncogenic activity of these genes (excluding FAM82B) was highly correlated with gene-copy numbers in tumor samples (correlation coefficient, r>0.423), indicating that amplifications of CENPF, GMNN, and CDK13 genes are tightly linked and coincident in tumors. Furthermore, we confirmed that CDK13 gene copy number was significantly associated with clinical onset age in patients with HCC (P = 0.0037). Taken together, our results suggest that coincidently amplified CDK13, GMNN, and CENPF genes can play a role as common cancer-driver genes in human cancers.

SUBMITTER: Kim HE

PROVIDER: S-EPMC3418236 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Frequent amplification of CENPF, GMNN and CDK13 genes in hepatocellular carcinomas.

Kim Hye-Eun HE Kim Dae-Ghon DG Lee Kyung Jin KJ Son Jang Geun JG Song Min-Young MY Park Young-Mi YM Kim Jae-Jung JJ Cho Sung-Won SW Chi Sung-Gil SG Cheong Hyun Sub HS Shin Hyoung Doo HD Lee Sang-Wook SW Lee Jong-Keuk JK

PloS one 20120813 8

Genomic changes frequently occur in cancer cells during tumorigenesis from normal cells. Using the Illumina Human NS-12 single-nucleotide polymorphism (SNP) chip to screen for gene copy number changes in primary hepatocellular carcinomas (HCCs), we initially detected amplification of 35 genes from four genomic regions (1q21-41, 6p21.2-24.1, 7p13 and 8q13-23). By integrated screening of these genes for both DNA copy number and gene expression in HCC and colorectal cancer, we selected CENPF (centr ...[more]

PMID: 22912832

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Project description:Hepatocellular carcinoma (HCC) is one of the most heterogeneous malignant cancers with no effective targets and treatments. However, the molecular pathogenesis of HCC remains largely uncertain. The aims of our study were to find crucial genes involved in HCC through multidimensional methods and revealed potential molecular mechanisms. Here, we reported the gene expression profile GSE121248 findings from 70 HCC and 37 adjacent normal tissues, all of which had chronic hepatitis B virus (HBV) infection, we were seeking to identify the dysregulated pathways, crucial genes and therapeutic targets implicated in HBV-associated HCC. We found 164 differentially expressed genes (DEGs) (92 downregulated genes and 72 upregulated genes). Gene ontology (GO) analysis of DEGs revealed significant functional enrichment of mitotic nuclear division, cell division, and the epoxygenase P450 pathway. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the DEGs were mainly enriched in metabolism, cell cycle regulation and the p53 signaling pathway. The Mcode plugin was calculated to construct a module complex of DEGs, and the module was mainly enriched in cell cycle checkpoints, RHO GTPase effectors and cytochrome P450. Considering a weak contribution of each gene, gene set enrichment analysis (GSEA) was performed, revealing results consistent with those described above. Six crucial proteins were selected based on the degree of centrality, including NDC80, ESR1, ZWINT, NCAPG, ENO3 and CENPF. Real-time quantitative PCR analysis validated the six crucial genes had the same expression trend as predicted. Furthermore, the methylation data of The Cancer Genome Atlas (TCGA) with HCC showed that mRNA expression of crucial genes was negatively correlated with methylation levels of their promoter region. The overall survival reflected that high expression of NDC80, CENPF, ZWINT, and NCAPG significantly predicted poor prognosis, whereas ESR1 high expression exhibited a favorable prognosis. The identification of the crucial genes and pathways would contribute to the development of novel molecular targets and biomarker-driven treatments for HCC.

Project description:BackgroundHepatocellular carcinoma (HCC) is a leading cause of tumor-associated death worldwide, owing to its high 5-year postoperative recurrence rate and inter-individual heterogeneity. Thus, a prognostic model is urgently needed for patients with HCC. Several researches have reported that copy number amplification of the 8q24 chromosomal region is associated with low survival in many cancers. In the present work, we set out to construct a multi-gene model for prognostic prediction in HCC.MethodsRNA sequencing and copy number variant data of tumor tissue samples of HCC from The Cancer Genome Atlas (n=328) were used to identify differentially expressed messenger RNAs of genes located on the chromosomal 8q24 region by the Wilcox test. Univariate Cox and Lasso-Cox regression analyses were carried out for the screening and construction of a prognostic multi-gene signature in The Cancer Genome Atlas cohort (n=119). The multi-gene signature was validated in a cohort from the International Cancer Genome Consortium (n=240). A nomogram for prognostic prediction was built, and the underpinning molecular mechanisms were studied by Gene Set Enrichment Analysis.ResultsWe successfully established a 7-gene prognostic signature model to predict the prognosis of patients with HCC. Using the model, we divided individuals into high-risk and low-risk sets, which showed a significant difference in overall survival in the training dataset (HR =0.17, 95% CI: 0.1-0.28; P<0.001) and in the testing dataset (HR = 0.42, 95% CI: 0.23-0.74; P=0.002). Multivariate Cox regression analysis showed the signature to be an independent prognostic factor of HCC survival. A nomogram including the prognostic signature was constructed and showed a better predictive performance in short-term (1 and 3 years) than in long-term (5 years) survival. Furthermore, Gene Set Enrichment Analysis identified several pathways of significance, which may aid in explaining the underlying molecular mechanism.ConclusionsOur 7-gene signature is a reliable prognostic marker for HCC, which may provide meaningful information for therapeutic customization and treatment-related decision making.

Project description:AimsDedifferentiated endometrial carcinomas (DDECs)/undifferentiated endometrial carcinomas (UECs) are aggressive endometrial cancers with frequent genomic inactivation of core components of switch/sucrose non-fermentable (SWI/SNF) complex proteins. Claudin-4, an epithelial intercellular tight junction protein, was recently found to be expressed in SWI/SNF-deficient undifferentiated carcinomas but not in SWI/SNF-deficient sarcomas. The aim of this study was to examine claudin-4 expression in UECs/DDECs and other high-grade uterine carcinomas.Methods and resultsWe examined claudin-4 expression by immunohistochemistry (clone 3E2C1) on tissue microarrays that contained 44 UECs/DDECs (24 SWI/SNF-deficient), 50 carcinosarcomas, 164 grade 3 endometrioid carcinomas, 57 serous carcinomas, and 20 clear cell carcinomas. Tumours with <5% claudin-4 expression were considered to be negative. Nearly all SWI/SNF-deficient, and most SWI/SNF-proficient, UECs/DDECs showed a complete absence of claudin-4 expression in the undifferentiated component, whereas the differentiated component in DDECs showed consistent and diffuse claudin-4 expression. Only one SWI/SNF-deficient DDEC showed focal expression of claudin-4 in the undifferentiated component, as compared with diffuse expression in the corresponding differentiated component. Claudin-4 expression was consistently absent in the sarcomatous component of carcinosarcoma, and it was absent in 24% of grade 3 endometrioid carcinomas and serous carcinomas.ConclusionClaudin-4 expression can be absent or very focal in a subset of high-grade endometrial carcinomas, and is almost always absent in the undifferentiated components of SWI/SNF-deficient UECs/DDECs, despite the apparent epithelial origin in the case of DDECs. Therefore, claudin-4 expression cannot be used to infer mesenchymal or epithelial tumour origin in the endometrium. The consistent loss or down-regulation of claudin-4, a tight junction protein, in SWI/SNF-deficient UECs/DDECs further supports the undifferentiated nature of these tumours.

Dataset Information

Frequent amplification of CENPF, GMNN and CDK13 genes in hepatocellular carcinomas.

Publications

Frequent amplification of CENPF, GMNN and CDK13 genes in hepatocellular carcinomas.

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