Gene Summary

Gene:CCNA1; cyclin A1
Aliases: CT146
Summary:The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. The cyclin encoded by this gene was shown to be expressed in testis and brain, as well as in several leukemic cell lines, and is thought to primarily function in the control of the germline meiotic cell cycle. This cyclin binds both CDK2 and CDC2 kinases, which give two distinct kinase activities, one appearing in S phase, the other in G2, and thus regulate separate functions in cell cycle. This cyclin was found to bind to important cell cycle regulators, such as Rb family proteins, transcription factor E2F-1, and the p21 family proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Skin Cancer
  • Neoplastic Cell Transformation
  • Cell Proliferation
  • Sensitivity and Specificity
  • DNA Methylation
  • Apoptosis
  • Head and Neck Cancers
  • Cancer Gene Expression Regulation
  • Chromosome 13
  • Case-Control Studies
  • Cervical Cancer
  • Promoter Regions
  • Polymerase Chain Reaction
  • Base Sequence
  • Repressor Proteins
  • Epigenetics
  • Molecular Sequence Data
  • Cyclin A1
  • Virus Integration
  • Cell Cycle
  • Bladder Cancer
  • Lung Cancer
  • Messenger RNA
  • Disease Progression
  • Statistics, Nonparametric
  • Breast Cancer
  • Proportional Hazards Models
  • Cervical Intraepithelial Neoplasia
  • Squamous Cell Carcinoma
  • Cell Movement
  • Cancer DNA
  • CCNA1
  • CpG Islands
  • Gene Silencing
  • Gene Expression Profiling
  • Biomarkers, Tumor
  • Cyclin A
  • Homeodomain Proteins
  • Staging
  • Papillomavirus Infections
  • Oligonucleotide Array Sequence Analysis
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CCNA1 (cancer-related)

Juodzbalys G, Kasradze D, Cicciù M, et al.
Modern molecular biomarkers of head and neck cancer. Part I. Epigenetic diagnostics and prognostics: Systematic review.
Cancer Biomark. 2016; 17(4):487-502 [PubMed] Related Publications
INTRODUCTION: Nearly half of the head and neck cancer cases are diagnosed in late stages. Traditional screening modalities have many disadvantages. The aim of the present article was to review the scientific literature about novel head and neck cancer diagnostics - epigenetic biomarkers.
EVIDENCE ACQUISITION: A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed database. Authors conducted the search of articles in English language published from 2004 to 2015.
EVIDENCE SYNTHESIS: A total of thirty three relevant studies were included in the review. Fifteen of them concerned DNA methylation alterations, nine evaluation of abundancies in histone expressions and nine miRNA expression changes in HNC.
CONCLUSIONS: Considerable number of epigenetic biomarkers have been identified in both tumor tissue and salivary samples. Genes with best diagnostic effectiveness rates and further studying prospects were: TIMP3, DCC, DAPK, CDH1, CCNA1, AIM1, MGMT, HIC1, PAX1, PAX5, ZIC4, p16, EDNRB, KIF1A, MINT31, CD44, RARβ , ECAD. Individual histone and miRNA alterations tend to be hnc specific. Prognostic values of separate biomarkers are ambiguous. No established standards for molecular assay of head and neck cancer was found in order to elude the paradoxical results and discrepancies in separate trials.

Koh YW, Chun SM, Park YS, et al.
Association between the CpG island methylator phenotype and its prognostic significance in primary pulmonary adenocarcinoma.
Tumour Biol. 2016; 37(8):10675-84 [PubMed] Related Publications
Aberrant methylation of promoter CpG islands is one of the most important inactivation mechanisms for tumor suppressor and tumor-related genes. Previous studies using genome-wide DNA methylation microarray analysis have suggested the existence of a CpG island methylator phenotype (CIMP) in lung adenocarcinomas. Although the biological behavior of these tumors varies according to tumor stage, no large-scale study has examined the CIMP in lung adenocarcinoma patients according to tumor stage. Furthermore, there have been no reported results regarding the clinical significance of each of the six CIMP markers. To examine the CIMP in patients with pulmonary adenocarcinoma after a surgical resection, we performed methylation analysis of six genes (CCNA1, ACAN, GFRA1, EDARADD, MGC45800, and p16 (INK4A)) in 230 pulmonary adenocarcinoma cases using the SEQUENOM MassARRAY platform. Fifty-four patients (28 %, 54/191) were in the CIMP-high (CIMP-H) group associated with high nodal stage (P = 0.007), the presence of micropapillary or solid histology (P = 0.003), and the absence of an epidermal growth factor receptor (EGFR) mutation (P = 0.002). By multivariate analysis, CIMP was an independent prognostic marker for overall survival (OS) and disease-specific survival (P = 0.03 and P = 0.43, respectively). In the stage I subgroups alone, CIMP-H patients had lower OS rates than the CIMP-low (CIMP-L) group (P = 0.041). Of the six CIMP markers, ACAN alone was significantly associated with patient survival. CIMP predicted the risk of progression independently of clinicopathological variables and enables the stratification of pulmonary adenocarcinoma patients, particularly among stage I cases.

Fang Y, Xie LN, Liu XM, et al.
Dysregulated module approach identifies disrupted genes and pathways associated with acute myelocytic leukemia.
Eur Rev Med Pharmacol Sci. 2015; 19(24):4811-26 [PubMed] Related Publications
OBJECTIVE: To identify disrupted genes and pathways involved in acute myelocytic leukemia (AML) by systematically tracking the dysregulated modules across normal and AML conditions.
MATERIALS AND METHODS: In this study, we firstly integrated the protein interaction data and expression profiles to infer and reweight the normal and AML networks using Pearson correlation coefficient (PCC). Next, clustering-based on maximal cliques (CMC) approach and a maximum weight bipartite matching method were implemented to infer the condition-specific modules and capture the disturbed modules, respectively, from two conditional networks. Then, the gene compositions and functional enrichment analysis were performed to identify the dysregulated genes and pathways. Finally, reverse transcription polymerase chain reaction (RT-PCR) was implemented to study the expression level of several key genes in AML patients.
RESULTS: In two conditional-specific networks, universal changes of gene correlations were revealed, making the differential correlation density among disrupted module pairs. In this work, a total of 84 altered modules were identified by comparing modules in normal and AML networks. Functional enrichment analysis showed that genes in altered modules mainly involved in cell cycle, nucleic acids and cancer signaling process, and differentially expressed genes (DEGs) and changed gene correlations were mainly participated in natural killer cell-mediated cytotoxicity and acute myeloid leukemia pathway. The key genes, such as MYC, EGFR, MAPK1 and CCNA1, were all significantly differentially expressed in AML patients.
CONCLUSIONS: This module approach effectively identifies dysregulated pathways and genes associated with AML. The considerable differences of gene correlations yield to these dysfunctional modules, and the coordinated disruption of these very modules contributes to leukemogenesis.

Huisman C, van der Wijst MG, Schokker M, et al.
Re-expression of Selected Epigenetically Silenced Candidate Tumor Suppressor Genes in Cervical Cancer by TET2-directed Demethylation.
Mol Ther. 2016; 24(3):536-47 [PubMed] Free Access to Full Article Related Publications
DNA hypermethylation is extensively explored as therapeutic target for gene expression modulation in cancer. Here, we re-activated hypermethylated candidate tumor suppressor genes (TSGs) (C13ORF18, CCNA1, TFPI2, and Maspin) by TET2-induced demethylation in cervical cancer cell lines. To redirect TET2 to hypermethylated TSGs, we engineered zinc finger proteins (ZFPs), which were first fused to the transcriptional activator VP64 to validate effective gene re-expression and confirm TSG function. ChIP-Seq not only revealed enriched binding of ZFPs to their intended sequence, but also considerable off-target binding, especially at promoter regions. Nevertheless, results obtained by targeted re-expression using ZFP-VP64 constructs were in line with cDNA overexpression; both revealed strong growth inhibition for C13ORF18 and TFPI2, but not for CCNA1 and Maspin. To explore effectivity of locus-targeted demethylation, ZFP-TET2 fusions were constructed which efficiently demethylated genes with subsequent gene re-activation. Moreover, targeting TET2 to TFPI2 and C13ORF18, but not CCNA1, significantly decreased cell growth, viability, and colony formation in cervical cancer cells compared to a catalytically inactive mutant of TET2. These data underline that effective re-activation of hypermethylated genes can be achieved through targeted DNA demethylation by TET2, which can assist in realizing sustained re-expression of genes of interest.

Virani S, Bellile E, Bradford CR, et al.
NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas.
BMC Cancer. 2015; 15:825 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: HPV-associated HNSCCs have a distinct etiologic mechanism and better prognosis than those with non-HPV associated HNSCCs. However, even within the each group, there is heterogeneity in survival time. Here, we test the hypothesis that specific candidate gene methylation markers (CCNA1, NDN, CD1A, DCC, p16, GADD45A) are associated with tumor recurrence and survival, in a well-characterized, prospective, cohort of 346 HNSCC patients.
METHODS: Kaplan-Meier curves were used to estimate survival time distributions. Multivariable Cox Proportional Hazards models were used to test associations between each methylation marker and OST/RPFT after adjusting for known or identified prognostic factors. Stratified Cox models included an interaction term between HPV and methylation marker to test for differences in the associations of the biomarker with OST or RPFT across HPV status.
RESULTS: Methylation markers were differentially associated with patient characteristics. DNA hypermethylation of NDN and CD1A was found to be significantly associated with overall survival time (OST) in all HNSCC patients (NDN hazard ratio (HR): 2.35, 95% CI: 1.40-3.94; CD1A HR: 1.31, 95% CI: 1.01-1.71). Stratification by HPV status revealed hypermethylation of CD1A was associated with better OST and recurrence/persistence-free time (RPFT) (OST HR: 3.34, 95% CI: 1.88-5.93; RPFT HR: 2.06, 95% CI: 1.21-3.49), while hypomethylation of CCNA1 was associated with increased RPFT in HPV (+) patients only (HR: 0.31, 95% CI: 0.13-0.74).
CONCLUSIONS: This study is the first to describe novel epigenetic alterations associated with survival in an unselected, prospectively collected, consecutive cohort of patients with HNSCC. DNA hypermethylation of NDN and CD1A was found to be significantly associated with increased overall survival time in all HNSCC patients. However, stratification by the important prognostic factor of HPV status revealed the immune marker, CD1A, and the cell cycle regulator, CCNA1 to be associated with prognosis in HPV (+) patients, specifically. Here, we identified novel methylation markers and specific, epigenetic molecular differences associated with HPV status, which warrant further investigation.

Yin A, Zhang Q, Kong X, et al.
JAM3 methylation status as a biomarker for diagnosis of preneoplastic and neoplastic lesions of the cervix.
Oncotarget. 2015; 6(42):44373-87 [PubMed] Free Access to Full Article Related Publications
DNA methylation is clinically relevant to important tumorigenic mechanisms. This study evaluated the methylation status of candidate genes in cervical neoplasia and determined their diagnostic performance in clinical practice. Cervical cancer and normal cervix tissue was used to select the top 5 discriminating loci among 27 loci in 4 genes (CCNA1, CADM1, DAPK1, JAM3), and one locus of JAM3 (region M4) was identified and confirmed with 267 and 224 cervical scrapings from 2 independent colposcopy referral studies. For patients with atypical squamous cells of unknown significance and those with low-grade squamous intraepithelial lesion, with JAM3-M4 compared to a triage marker of hrHPV testing, the specificity for cervical intraepithelial neoplasia 3 CIN3 and cancer cases (CIN3+) / no neoplasia and CIN1 (CIN1-) was significantly increased, from 21.88 to 81.82 and 15.38 to 85.18, respectively. The corresponding positive predictive value (PPV) was increased from 26.47 to 57.14 and 18.52 to 63.64, respectively. For hrHPV-positive patients, compared to a triage marker of cytology testing, JAM3-M4 showed increased specificity and PPV, from 30.67 to 87.65 and 38.82 to 82.14, respectively. We assessed whether JAM3-M4 could distinguish productive from transforming CIN2; the coincidence rate of JAM3-M4 and P16 was as high as 60.5%.

Waraya M, Yamashita K, Ema A, et al.
Exclusive Association of p53 Mutation with Super-High Methylation of Tumor Suppressor Genes in the p53 Pathway in a Unique Gastric Cancer Phenotype.
PLoS One. 2015; 10(10):e0139902 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A comprehensive search for DNA methylated genes identified candidate tumor suppressor genes that have been proven to be involved in the apoptotic process of the p53 pathway. In this study, we investigated p53 mutation in relation to such epigenetic alteration in primary gastric cancer.
METHODS: The methylation profiles of the 3 genes: PGP9.5, NMDAR2B, and CCNA1, which are involved in the p53 tumor suppressor pathway in combination with p53 mutation were examined in 163 primary gastric cancers. The effect of epigenetic reversion in combination with chemotherapeutic drugs on apoptosis was also assessed according to the tumor p53 mutation status.
RESULTS: p53 gene mutations were found in 44 primary gastric tumors (27%), and super-high methylation of any of the 3 genes was only found in cases with wild type p53. Higher p53 pathway aberration was found in cases with male gender (p = 0.003), intestinal type (p = 0.005), and non-infiltrating type (p = 0.001). The p53 pathway aberration group exhibited less recurrence in lymph nodes, distant organs, and peritoneum than the p53 non-aberration group. In the NUGC4 gastric cancer cell line (p53 wild type), epigenetic treatment augmented apoptosis by chemotherapeutic drugs, partially through p53 transcription activity. On the other hand, in the KATO III cancer cell line (p53 mutant), epigenetic treatment alone induced robust apoptosis, with no trans-activation of p53.
CONCLUSION: In gastric cancer, p53 relevant and non-relevant pathways exist, and tumors with either pathway type exhibited unique clinical features. Epigenetic treatments can induce apoptosis partially through p53 activation, however their apoptotic effects may be explained largely by mechanism other than through p53 pathways.

Chalertpet K, Pakdeechaidan W, Patel V, et al.
Human papillomavirus type 16 E7 oncoprotein mediates CCNA1 promoter methylation.
Cancer Sci. 2015; 106(10):1333-40 [PubMed] Free Access to Full Article Related Publications
Human papillomavirus (HPV) oncoproteins drive distinctive promoter methylation patterns in cancer. However, the underlying mechanism remains to be elucidated. Cyclin A1 (CCNA1) promoter methylation is strongly associated with HPV-associated cancer. CCNA1 methylation is found in HPV-associated cervical cancers, as well as in head and neck squamous cell cancer. Numerous pieces of evidence suggest that E7 may drive CCNA1 methylation. First, the CCNA1 promoter is methylated in HPV-positive epithelial lesions after transformation. Second, the CCNA1 promoter is methylated at a high level when HPV is integrated into the human genome. Finally, E7 has been shown to interact with DNA methyltransferase 1 (Dnmt1). Here, we sought to determine the mechanism by which E7 increases methylation in cervical cancer by using CCNA1 as a gene model. We investigated whether E7 induces CCNA1 promoter methylation, resulting in the loss of expression. Using both E7 knockdown and overexpression approaches in SiHa and C33a cells, our data showed that CCNA1 promoter methylation decreases with a corresponding increase in expression in E7 siRNA-transfected cells. By contrast, CCNA1 promoter methylation was augmented with a corresponding reduction in expression in E7-overexpressing cells. To confirm whether the binding of the E7-Dnmt1 complex to the CCNA1 promoter induced methylation and loss of expression, ChIP assays were carried out in E7-, del CR3-E7 and vector control-overexpressing C33a cells. The data showed that E7 induced CCNA1 methylation by forming a complex with Dnmt1 at the CCNA1 promoter, resulting in the subsequent reduction of expression in cancers. It is interesting to further explore the genome-wide mechanism of E7 oncoprotein-mediated DNA methylation.

Feng Y, Li L, Zhang X, et al.
Hematopoietic pre-B cell leukemia transcription factor interacting protein is overexpressed in gastric cancer and promotes gastric cancer cell proliferation, migration, and invasion.
Cancer Sci. 2015; 106(10):1313-22 [PubMed] Free Access to Full Article Related Publications
Hematopoietic pre-B cell leukemia transcription factor interacting protein (HPIP) has been shown to play an important role in the development and progression of some cancers. However, the role of HPIP in gastric cancer (GC) is unclear. Here, we show that HPIP is upregulated in most GC patients and promotes GC cell proliferation, migration, and invasion. In GC patients, HPIP positively associates with tumor size and nodal metastasis, and negatively associates with tumor differentiation. Hematopoietic pre-B cell leukemia transcription factor interacting protein increases GC cell proliferation through activation of G1 /S and G2 /M cell cycle transitions, accompanied by a marked increase of the positive cell cycle regulators, including cyclin D1, cyclin A, and cyclin B1. Hematopoietic pre-B cell leukemia transcription factor interacting protein enhances GC cell migration and invasion, and modulates epithelial-mesenchymal transition, which plays a key role in cancer cell migration and invasion. These data underscore the critical role of HPIP in GC cell proliferation and progression and suggest that HPIP inhibition may be a useful therapeutic strategy for GC treatment.

Milutin Gašperov N, Sabol I, Planinić P, et al.
Methylated Host Cell Gene Promoters and Human Papillomavirus Type 16 and 18 Predicting Cervical Lesions and Cancer.
PLoS One. 2015; 10(6):e0129452 [PubMed] Free Access to Full Article Related Publications
Change in the host and/or human papillomavirus (HPV) DNA methylation profile is probably one of the main factors responsible for the malignant progression of cervical lesions to cancer. To investigate those changes we studied 173 cervical samples with different grades of cervical lesion, from normal to cervical cancer. The methylation status of nine cellular gene promoters, CCNA1, CDH1, C13ORF18, DAPK1, HIC1, RARβ2, hTERT1, hTERT2 and TWIST1, was investigated by Methylation Specific Polymerase Chain Reaction (MSP). The methylation of HPV18 L1-gene was also investigated by MSP, while the methylated cytosines within four regions, L1, 5'LCR, enhancer, and promoter of the HPV16 genome covering 19 CpG sites were evaluated by bisulfite sequencing. Statistically significant methylation biomarkers distinguishing between cervical precursor lesions from normal cervix were primarily C13ORF18 and secondly CCNA1, and those distinguishing cervical cancer from normal or cervical precursor lesions were CCNA1, C13ORF18, hTERT1, hTERT2 and TWIST1. In addition, the methylation analysis of individual CpG sites of the HPV16 genome in different sample groups, notably the 7455 and 7694 sites, proved to be more important than the overall methylation frequency. The majority of HPV18 positive samples contained both methylated and unmethylated L1 gene, and samples with L1-gene methylated forms alone had better prognosis when correlated with the host cell gene promoters' methylation profiles. In conclusion, both cellular and viral methylation biomarkers should be used for monitoring cervical lesion progression to prevent invasive cervical cancer.

Chen X, Liu L, Mims J, et al.
Analysis of DNA methylation and gene expression in radiation-resistant head and neck tumors.
Epigenetics. 2015; 10(6):545-61 [PubMed] Free Access to Full Article Related Publications
Resistance to radiation therapy constitutes a significant challenge in the treatment of head and neck squamous cell cancer (HNSCC). Alteration in DNA methylation is thought to play a role in this resistance. Here, we analyzed DNA methylation changes in a matched model of radiation resistance for HNSCC using the Illumina HumanMethylation450 BeadChip. Our results show that compared to radiation-sensitive cells (SCC-61), radiation-resistant cells (rSCC-61) had a significant increase in DNA methylation. After combining these results with microarray gene expression data, we identified 84 differentially methylated and expressed genes between these 2 cell lines. Ingenuity Pathway Analysis revealed ILK signaling, glucocorticoid receptor signaling, fatty acid α-oxidation, and cell cycle regulation as top canonical pathways associated with radiation resistance. Validation studies focused on CCND2, a protein involved in cell cycle regulation, which was identified as hypermethylated in the promoter region and downregulated in rSCC-61 relative to SCC-61 cells. Treatment of rSCC-61 and SCC-61 with the DNA hypomethylating agent 5-aza-2'deoxycitidine increased CCND2 levels only in rSCC-61 cells, while treatment with the control reagent cytosine arabinoside did not influence the expression of this gene. Further analysis of HNSCC data from The Cancer Genome Atlas found increased methylation in radiation-resistant tumors, consistent with the cell culture data. Our findings point to global DNA methylation status as a biomarker of radiation resistance in HNSCC, and suggest a need for targeted manipulation of DNA methylation to increase radiation response in HNSCC.

Jeon YK, Park SG, Choi IW, et al.
Cancer cell-associated cytoplasmic B7-H4 is induced by hypoxia through hypoxia-inducible factor-1α and promotes cancer cell proliferation.
Biochem Biophys Res Commun. 2015; 459(2):277-83 [PubMed] Related Publications
Aberrant B7-H4 expression in cancer tissues serves as a novel prognostic biomarker for poor survival in patients with cancer. However, the factor(s) that induce cancer cell-associated B7-H4 remain to be fully elucidated. We herein demonstrate that hypoxia upregulates B7-H4 transcription in primary CD138(+) multiple myeloma cells and cancer cell lines. In support of this finding, analysis of the Multiple Myeloma Genomics Portal (MMGP) data set revealed a positive correlation between the mRNA expression levels of B7-H4 and the endogenous hypoxia marker carbonic anhydrogenase 9. Hypoxia-induced B7-H4 expression was detected in the cytoplasm, but not in cancer cell membranes. Chromatin immunoprecipitation analysis demonstrated binding of hypoxia-inducible factor-1α (HIF-1α) to proximal hypoxia-response element (HRE) sites within the B7-H4 promoter. Knockdown of HIF-1α and pharmacological inhibition of HIF-1α diminished B7-H4 expression. Furthermore, knockdown of cytoplasmic B7-H4 in MCF-7 decreased the S-phase cell population under hypoxia. Finally, MMGP analysis revealed a positive correlation between the transcript levels of B7-H4 and proliferation-related genes including MKI67, CCNA1, and Myc in several patients with multiple myeloma. Our results provide insight into the mechanisms underlying B7-H4 upregulation and its role in cancer cell proliferation in a hypoxic tumor microenvironment.

Lee YS, Ryu SW, Bae SJ, et al.
Cross-platform meta-analysis of multiple gene expression profiles identifies novel expression signatures in acquired anthracycline-resistant breast cancer.
Oncol Rep. 2015; 33(4):1985-93 [PubMed] Related Publications
Anthracyclines are among the most effective and commonly used chemotherapeutic agents. However, the development of acquired anthracycline resistance is a major limitation to their clinical application. The aim of the present study was to identify differentially expressed genes (DEGs) and biological processes associated with the acquisition of anthracycline resistance in human breast cancer cells. We performed a meta-analysis of publically available microarray datasets containing data on stepwise-selected, anthracycline‑resistant breast cancer cell lines using the RankProd package in R. Additionally, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to analyze GO term enrichment and pathways, respectively. A protein-protein interaction (PPI) network was also generated using Cytoscape software. The meta-analysis yielded 413 DEGs related to anthracycline resistance in human breast cancer cells, and 374 of these were not involved in individual DEGs. GO analyses showed the 413 genes were enriched with terms such as 'response to steroid metabolic process', 'chemical stimulus', 'external stimulus', 'hormone stimulus', 'multicellular organismal process', and 'system development'. Pathway analysis revealed significant pathways including steroid hormone biosynthesis, cytokine-cytokine receptor interaction, drug metabolism-cytochrome P450, metabolism of xenobiotics by cytochrome P450, and arachidonic acid metabolism. The PPI network indicated that proteins encoded by TRIM29, VTN, CCNA1, and karyopherin α 5 (KPNA5) participated in a significant number of interactions. In conclusion, our meta-analysis provides a comprehensive view of gene expression patterns associated with acquired resistance to anthracycline in breast cancer cells, and constitutes the basis for additional functional studies.

Arantes LM, de Carvalho AC, Melendez ME, et al.
Validation of methylation markers for diagnosis of oral cavity cancer.
Eur J Cancer. 2015; 51(5):632-41 [PubMed] Related Publications
PURPOSE: Activation of proto-oncogenes and inactivation of tumour suppressor genes are the major genetic alterations involved in carcinogenesis. The increase in methylation at the promoter region of a tumour suppressor gene can lead to gene inactivation, selecting cells with proliferative advantage. Thus, promoter hypermethylation is considered a marker in a variety of malignant tumours, including oral cavity.
EXPERIMENTAL DESIGN: The methylation pattern of eight genes was evaluated in 40 oral cavity squamous cell carcinomas (OSCCs) and 40 saliva samples from healthy individuals by Q-MSP. Different combinations of genes were also assessed in order to identify gene panels that could better distinguish between OSCC and saliva samples.
RESULTS: CCNA1, DAPK, DCC and TIMP3 methylation were highly specific for being found in the OSCC samples. Moreover, the combination of these genes improved detection when compared with single markers, reaching values of 92.5% for sensitivity and specificity (when using the panel CCNA1, DCC, TIMP3). Moreover, DAPK, DCC and TIMP3 were hypermethylated in nearly 90% of clinically T1 and T2 cases.
CONCLUSION: The pursuing of this panel of hypermethylated genes is an important tool for the detection of individuals with OSCC. Moreover, the identification of these markers in early stages of OSCC shows the feasibility of using the panel on saliva as possible biomarkers for early diagnosis. The lack of association between the methylation status of these genes and clinical characteristics shows that they are able to distinguish OSCC cases irrespective of social and clinical factors (gender, age, human papillomavirus (HPV) status, clinical stage, vascular embolisation and perineural invasion).

Yang B, Miao S, Zhang LN, et al.
Correlation of CCNA1 promoter methylation with malignant tumors: a meta-analysis introduction.
Biomed Res Int. 2015; 2015:134027 [PubMed] Free Access to Full Article Related Publications
Epigenetic silencing of tumor suppressor genes by promoter methylation plays vital roles in the process of carcinogenesis. The purpose of this meta-analysis was to determine whether the aberrant methylation of cyclin A1 (CCNA1) may be of great significance to human malignant tumors. By searching both English and Chinese language-based electronic databases carefully, we tabulated and analyzed parameters from each study. All human-associated case-control studies were included providing available data for CCNA1 methylation and reporting the adjusted odds ratios (ORs) and 95% confidence intervals (CI) conducted with the use of Version 12.0 STATA software. A total of 10 case-control studies (619 patients with cancers and 292 healthy controls) were included for the following statistical analysis. Pooled OR values from all articles revealed that the frequency of CCNA1 methylation in cancer tissues was significantly higher than those of normal tissues (P < 0.001). Further ethnicity indicated that the frequency of CCNA1 methylation was correlated with the development of malignant tumors among all those included experimental subgroups (all P < 0.05). These data from results indicated a significant connection of CCNA1 methylation with poor progression in human malignant tumors among both Caucasian and Asian populations.

Richmond J, Carol H, Evans K, et al.
Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia.
Clin Cancer Res. 2015; 21(6):1395-405 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Although the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (∼50%). Mutations in the p53 tumor-suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts.
EXPERIMENTAL DESIGN: Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell-cycle arrest, and apoptosis in vivo was evaluated.
RESULTS: Gene-expression analysis revealed that MLL-ALL, B-lineage ALL, and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be overexpressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly upregulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 upregulation, cell-cycle arrest, and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft.
CONCLUSIONS: The utility of targeting the p53-MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation.

Pan W, Li G, Yang X, Miao J
Revealing the potential pathogenesis of glioma by utilizing a glioma associated protein-protein interaction network.
Pathol Oncol Res. 2015; 21(2):455-62 [PubMed] Related Publications
This study aims to explore the potential mechanism of glioma through bioinformatic approaches. The gene expression profile (GSE4290) of glioma tumor and non-tumor samples was downloaded from Gene Expression Omnibus database. A total of 180 samples were available, including 23 non-tumor and 157 tumor samples. Then the raw data were preprocessed using robust multiarray analysis, and 8,890 differentially expressed genes (DEGs) were identified by using t-test (false discovery rate < 0.0005). Furthermore, 16 known glioma related genes were abstracted from Genetic Association Database. After mapping 8,890 DEGs and 16 known glioma related genes to Human Protein Reference Database, a glioma associated protein-protein interaction network (GAPN) was constructed. In addition, 51 sub-networks in GAPN were screened out through Molecular Complex Detection (score ≥ 1), and sub-network 1 was found to have the closest interaction (score = 3). What' more, for the top 10 sub-networks, Gene Ontology (GO) enrichment analysis (p value < 0.05) was performed, and DEGs involved in sub-network 1 and 2, such as BRMS1L and CCNA1, were predicted to regulate cell growth, cell cycle, and DNA replication via interacting with known glioma related genes. Finally, the overlaps of DEGs and human essential, housekeeping, tissue-specific genes were calculated (p value = 1.0, 1.0, and 0.00014, respectively) and visualized by Venn Diagram package in R. About 61% of human tissue-specific genes were DEGs as well. This research shed new light on the pathogenesis of glioma based on DEGs and GAPN, and our findings might provide potential targets for clinical glioma treatment.

Zubor P, Hatok J, Moricova P, et al.
Gene expression profiling of histologically normal breast tissue in females with human epidermal growth factor receptor 2‑positive breast cancer.
Mol Med Rep. 2015; 11(2):1421-7 [PubMed] Related Publications
Gene expression profile‑based taxonomy of breast cancer (BC) has been described as a significant breakthrough in comprehending the differences in the origin and behavior of cancer to allow individually tailored therapeutic approaches. In line with this, we hypothesized that the gene expression profile of histologically normal epithelium (HNEpi) could harbor certain genetic abnormalities predisposing breast tissue cells to develop human epidermal growth factor receptor 2 (HER2)‑positive BC. Thus, the aim of the present study was to assess gene expression in normal and BC tissue (BCTis) from patients with BC in order to establish its value as a potential diagnostic marker for cancer development. An array study evaluating a panel of 84 pathway‑ and disease‑specific genes in HER2‑positive BC and tumor‑adjacent HNEpi was performed using quantitative polymerase chain reaction in 12 patients using microdissected samples from frozen tissue. Common prognostic and predictive parameters of BC were assessed by immunohistochemistry and in situ hybridization. In the BCTis and HNEpi samples of 12 HER2‑positive subjects with BC, the expression of 2,016 genes was assessed. A total of 39.3% of genes were deregulated at a minimal two‑fold deregulation rate and 10.7% at a five‑fold deregulation rate in samples of HNEpi or BCTis. Significant differences in gene expression between BCTis and HNEpi samples were revealed for BCL2L2, CD44, CTSD, EGFR, ERBB2, ITGA6, NGFB, RPL27, SCBG2A1 and SCGB1D2 genes (P<0.05), as well as GSN, KIT, KLK5, SERPINB5 and STC2 genes (P<0.01). Insignificant differences (P<0.07) were observed for CCNA1, CLU, DLC1, GABRP and IL6 genes. The ontological gene analyses revealed that the majority of the deregulated genes in the HNEpi samples were part of the functional gene group directly associated with BC origin and prognosis. Functional analysis showed that the most frequent gene deregulations occurred in genes associated with apoptosis and cell cycle regulation in BCTis samples, and with angiogenesis, regulation of the cell cycle and transcriptional activity in HNEpi samples. The molecular profiling of HNEpi breast tissue revealed gene expression abnormalities that may represent potential markers of increased risk for HER2‑positive malignant transformation of breast tissue, and may be able to be employed as predictors of prognosis.

Klajic J, Busato F, Edvardsen H, et al.
DNA methylation status of key cell-cycle regulators such as CDKNA2/p16 and CCNA1 correlates with treatment response to doxorubicin and 5-fluorouracil in locally advanced breast tumors.
Clin Cancer Res. 2014; 20(24):6357-66 [PubMed] Related Publications
PURPOSE: To explore alterations in gene promoter methylation as a potential cause of acquired drug resistance to doxorubicin or combined treatment with 5-fluorouracil and mitomycin C in human breast cancers.
EXPERIMENTAL DESIGN: Paired tumor samples from locally advanced breast cancer patients treated with doxorubicin and 5-fluorouracil-mitomycin C were used in the genome-wide DNA methylation analysis as discovery cohort. An enlarged cohort from the same two prospective studies as those in the discovery cohort was used as a validation set in pyrosequencing analysis.
RESULTS: A total of 469 genes were differentially methylated after treatment with doxorubicin and revealed a significant association with canonical pathways enriched for immune cell response and cell-cycle regulating genes including CDKN2A, CCND2, CCNA1, which were also associated to treatment response. Treatment with FUMI resulted in 343 differentially methylated genes representing canonical pathways such as retinoate biosynthesis, gαi signaling, and LXR/RXR activation. Despite the clearly different genes and pathways involved in the metabolism and therapeutic effect of both drugs, 46 genes were differentially methylated before and after treatment with both doxorubicin and FUMI. DNA methylation profiles in genes such as BRCA1, FOXC1, and IGFBP3, and most notably repetitive elements like ALU and LINE1, were associated with TP53 mutations status.
CONCLUSION: We identified and validated key cell-cycle regulators differentially methylated before and after neoadjuvant chemotherapy such as CDKN2A and CCNA1 and reported that methylation patterns of these genes may be potential predictive markers to anthracycline/mitomycine sensitivity.

Chujan S, Kitkumthorn N, Siriangkul S, Mutirangura A
CCNA1 promoter methylation: a potential marker for grading Papanicolaou smear cervical squamous intraepithelial lesions.
Asian Pac J Cancer Prev. 2014; 15(18):7971-5 [PubMed] Related Publications
BACKGROUND: From our previous study, we established that cyclin A1 (CCNA1) promoter methylation is strongly correlated with multistep progression of HPV-associated cervical cancer, suggesting potential use as a diagnostic maker of disease.
OBJECTIVES: The purpose of the present study was to assess the prevalence of CCNA1 promoter methylation in residual cervical cells isolated from liquid-based cytology that underwent hrHPV DNA screening for cervical cancer, and then to evaluate this marker for diagnostic accuracy using parameters like sensitivity, specificity, predictive values and likelihood ratio.
METHODS: In this retrospective study, histopathology was used as the gold standard method with specimens separated into the following groups: negative (n=31), low- grade squamous intraepithelial lesions (LSIL, n=34) and high-grade squamous intraepithelial lesions or worse (HSIL+, n=32). The hrHPV was detected by Hybrid Capture 2 (HC2) and CCNA1 promoter methylation was examined by CCNA1 duplex methylation specific PCR.
RESULTS: The results showed the frequencies of CCNA1 promoter methylation were 0%, 5.88% and 83.33%, while the percentages of hrHPV were 66.67%, 82.35% and 100% in the negative, LSIL and HSIL+ groups, respectively. Although hrHPV infection showed high frequency in all three groups, it could not differentiate between the different groups and grades of precancerous lesions. In contrast, CCNA1 promoter methylation clearly distinguished between negative/LSIL and HSIL+, with high levels of all statistic parameters.
CONCLUSION: CCNA1 promoter methylation is a potential marker for distinguishing between histologic negative/LSIL and HSIL+using cervical cytology samples.

Tan JK, Tan EL, Gan SY
Elucidating the roles of miR-372 in cell proliferation and apoptosis of nasopharyngeal carcinoma TW01 cells.
Exp Oncol. 2014; 36(3):170-3 [PubMed] Related Publications
AIM: Deregulation of microRNA has been associated with cancer progression and the modification of cancer phenotypes could be achieved by targeting microRNA expression. This study aimed to determine the effects of miR-372 on cell progression and gene expression in nasopharyngeal carcinoma cell line, TW01.
MATERIALS AND METHODS: NPC TW01 cells were transfected with the miR-372 precursor molecules. Gene expression studies were conducted using RT-PCR assays for nine cancer related genes. The effects of miR-372 on cell proliferation, cell cycle arrest and apoptosis were also investigated.
RESULTS: Expression of -miR-372 caused cell cycle arrest at the S phase that was accompanied by an overall decrease of cells entering the G2/M phase. miR-372 did not have any significant effect on apoptosis. Of the nine genes studied, four were up-regulated, namely CDKN1A, INCA1, LATS2 and BIRC5. The other five genes - CDK2, CCNA1, TP53, BAX and BCL2 were down-regulated by miR-372.
CONCLUSION: This preliminary study indicated the tumor suppressing roles of miR-372 in cell cycle progression of TW01 cells, possibly via the down-regulation of CDK2 and CCNA1 as well as the up-regulation of CDKN1A and INCA1.Key Words: apoptosis, microRNA, nasopharyngeal carcinoma, miR-372, CDK2, CCNA1.

Zuo Q, Zheng W, Zhang J, et al.
Methylation in the promoters of HS3ST2 and CCNA1 genes is associated with cervical cancer in Uygur women in Xinjiang.
Int J Biol Markers. 2014; 29(4):e354-62 [PubMed] Related Publications
We assessed the suitability of HS3ST2 and CCNA1 genes as biomarkers for the early detection of cervical cancer in Uygur women in Xinjiang, China. Methylation-specific PCR (MSP) and HPV (HPV16 and HPV18)-specific PCR were performed on 110 cervical samples: 40 normal cervices, 10 cervical intraepithelial neoplasia 1 (CIN1), 10 CIN2, 10 CIN3 and 40 cervical cancer tissues. The expression of the 2 genes was measured by reverse transcription PCR (RT-PCR) in 10 methylation-positive and 10 methylation-negative cervical tissues. We found that both HS3ST2 and CCNA1 genes were methylated in 38 of the 40 cervical cancer tissues, 9 of the 10 CIN3, and 6 of the 10 CIN2. In contrast, methylation of these 2 genes was found in only 1 of the 40 normal tissues and none of 10 CIN1. Furthermore, hypermethylated HS3ST2 and CCNA1 genes were correlated with infection with HPV16 and HPV18 in high-grade squamous intraepithelial lesions (HSILs) and cervical cancer (both p<0.05). The expression of HS3ST2 and CCNA1 genes was lower in the methylation-positive cervical tissues than in the methylation-negative cervical tissues. Our results indicate that HS3ST2 and CCNA1 genes may play important roles in HPV-induced cervical cancer and that patients with specific hypermethylated genes may have a greater risk of progressing to invasive cervical cancer.

Liang Q, Yao X, Tang S, et al.
Integrative identification of Epstein-Barr virus-associated mutations and epigenetic alterations in gastric cancer.
Gastroenterology. 2014; 147(6):1350-62.e4 [PubMed] Related Publications
BACKGROUND & AIMS: The mechanisms by which Epstein-Barr virus (EBV) contributes to the development of gastric cancer are unclear. We investigated EBV-associated genomic and epigenomic variations in gastric cancer cells and tumors.
METHODS: We performed whole-genome, transcriptome, and epigenome sequence analyses of a gastric adenocarcinoma cell line (AGS cells), before and after EBV infection. We then looked for alterations in gastric tumor samples, with (n = 34) or without (n = 100) EBV infection, collected from patients at the Prince of Wales Hospital, Chinese University of Hong Kong (from 1998 through 2004), or the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (from 1999 through 2006).
RESULTS: Transcriptome analysis showed that infected cells expressed 9 EBV genes previously detected in EBV-associated gastric tumors and 71 EBV genes not previously reported in gastric tumors. Ten viral genes that had not been reported previously in gastric cancer but were expressed most highly in EBV-infected cells also were expressed in primary EBV-positive gastric tumors. Whole-genome sequence analysis identified 45 EBV-associated nonsynonymous mutations. These mutations, in genes such as AKT2, CCNA1, MAP3K4, and TGFBR1, were associated significantly with EBV-positive gastric tumors, compared with EBV-negative tumors. An activating mutation in AKT2 was associated with reduced survival times of patients with EBV-positive gastric cancer (P = .006); this mutation was found to dysregulate mitogen-activated protein kinase signaling. Integrated epigenome and transcriptome analyses identified 216 genes transcriptionally down-regulated by EBV-associated hypermethylation; methylation of ACSS1, FAM3B, IHH, and TRABD increased significantly in EBV-positive tumors. Overexpression of Indian hedgehog (IHH) and TraB domain containing (TRABD) increased proliferation and colony formation of gastric cancer cells, whereas knockdown of these genes reduced these activities. We found 5 signaling pathways (axon guidance, focal adhesion formation, interactions among cytokines and receptors, mitogen-activated protein kinase signaling, and actin cytoskeleton regulation) to be affected commonly by EBV-associated genomic and epigenomic alterations.
CONCLUSIONS: By using genomic, transcriptome, and epigenomic comparisons of EBV infected vs noninfected gastric cancer cells and tumor samples, we identified alterations in genes, gene expression, and methylation that affect different signaling networks. These might be involved in EBV-associated gastric carcinogenesis.

Tudoran O, Virtic O, Balacescu L, et al.
Differential peripheral blood gene expression profile based on Her2 expression on primary tumors of breast cancer patients.
PLoS One. 2014; 9(7):e102764 [PubMed] Free Access to Full Article Related Publications
Breast cancer prognosis and treatment is highly dependent on the molecular features of the primary tumors. These tumors release specific molecules into the environment that trigger characteristic responses into the circulatory cells. In this study we investigated the expression pattern of 84 genes known to be involved in breast cancer signaling in the peripheral blood of breast cancer patients with ER-, PR- primary tumors. The patients were grouped according to Her2 expression on the primary tumors in Her2+ and Her2- cohorts. Transcriptional analysis revealed 15 genes to be differentially expressed between the two groups highlighting that Her2 signaling in primary tumors could be associated with specific blood gene expression. We found CCNA1 to be up-regulated, while ERBB2, RASSF1, CDH1, MKI67, GATA3, GLI1, SFN, PTGS2, JUN, NOTCH1, CTNNB1, KRT8, SRC, and HIC1 genes were down-regulated in the blood of triple negative breast cancer patients compared to Her2+ cohort. IPA network analysis predicts that the identified genes are interconnected and regulate each other. These genes code for cell cycle regulators, cell adhesion molecules, transcription factors or signal transducers that modulate immune signaling, several genes being also associated with cancer progression and treatment response. These results indicate an altered immune signaling in the peripheral blood of triple negative breast cancer patients. The involvement of the immune system is necessary in favorable treatment response, therefore these results could explain the low response rates observed for triple negative breast cancer patients.

Maldonado L, Brait M, Michailidi C, et al.
An epigenetic marker panel for recurrence risk prediction of low grade papillary urothelial cell carcinoma (LGPUCC) and its potential use for surveillance after transurethral resection using urine.
Oncotarget. 2014; 5(14):5218-33 [PubMed] Free Access to Full Article Related Publications
By a candidate gene approach, we analyzed the promoter methylation (PM) of 8 genes genes (ARF, TIMP3, RAR-β2, NID2, CCNA1, AIM1, CALCA and CCND2) by quantitative methylation specific PCR (QMSP) in DNA of 17 non-recurrent and 19 recurrent noninvasive low grade papillary urothelial cell carcinoma (LGPUCC) archival tissues. Among the genes tested, by establishing an empiric cutoff value, CCND2, CCNA1, NID2, and CALCA showed higher frequency of methylation in recurrent than in non-recurrent LGPUCC: CCND2 10/19 (53%) vs. 2/17 (12%) (p=0.014); CCNA1 11/19 (58%) vs. 4/17 (23.5%) (p=0.048); NID2 13/19 (68%) vs. 3/17 (18%) (p=0.003) and CALCA 10/19 (53%) vs. 4/17 (23.5%) (p=0.097), respectively. We further analyzed PM of CCND2, CCNA1, and CALCA in urine DNA from UCC patients including LGPUCC and controls. The frequency of CCND2, CCNA1 and CALCA was significantly higher (p<0.0001) in urine of UCC cases [ 38/148 (26%), 50/73 (68%) and 94/148 (63.5%) respectively] than controls [0/56 (0%), 10/60 (17%) and 16/56 (28.5%), respectively)]. Most importantly we found any one of the 3 markers methylation positive in 25 out of 30 (83%) cytology negative LGPUCC cases. We also explored the biological function of CCNA1 in UCC. Prospective confirmatory studies are needed to develop a reliable tool for prediction of recurrence using primary LGPUCC tissues and/or urine.

Loh M, Liem N, Vaithilingam A, et al.
DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: a comprehensive profiling approach.
BMC Gastroenterol. 2014; 14:55 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Methylation-induced silencing of promoter CpG islands in tumor suppressor genes plays an important role in human carcinogenesis. In colorectal cancer, the CpG island methylator phenotype (CIMP) is defined as widespread and elevated levels of DNA methylation and CIMP+ tumors have distinctive clinicopathological and molecular features. In contrast, the existence of a comparable CIMP subtype in gastric cancer (GC) has not been clearly established. To further investigate this issue, in the present study we performed comprehensive DNA methylation profiling of a well-characterised series of primary GC.
METHODS: The methylation status of 1,421 autosomal CpG sites located within 768 cancer-related genes was investigated using the Illumina GoldenGate Methylation Panel I assay on DNA extracted from 60 gastric tumors and matched tumor-adjacent gastric tissue pairs. Methylation data was analysed using a recursively partitioned mixture model and investigated for associations with clinicopathological and molecular features including age, Helicobacter pylori status, tumor site, patient survival, microsatellite instability and BRAF and KRAS mutations.
RESULTS: A total of 147 genes were differentially methylated between tumor and matched tumor-adjacent gastric tissue, with HOXA5 and hedgehog signalling being the top-ranked gene and signalling pathway, respectively. Unsupervised clustering of methylation data revealed the existence of 6 subgroups under two main clusters, referred to as L (low methylation; 28% of cases) and H (high methylation; 72%). Female patients were over-represented in the H tumor group compared to L group (36% vs 6%; P = 0.024), however no other significant differences in clinicopathological or molecular features were apparent. CpG sites that were hypermethylated in group H were more frequently located in CpG islands and marked for polycomb occupancy.
CONCLUSIONS: High-throughput methylation analysis implicates genes involved in embryonic development and hedgehog signaling in gastric tumorigenesis. GC is comprised of two major methylation subtypes, with the highly methylated group showing some features consistent with a CpG island methylator phenotype.

Rettori MM, de Carvalho AC, Longo AL, et al.
TIMP3 and CCNA1 hypermethylation in HNSCC is associated with an increased incidence of second primary tumors.
J Transl Med. 2013; 11:316 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hypermethylation in the promoter regions is associated with the suppression of gene expression and has been considered a potential molecular marker for several tumor types, including head and neck squamous cell carcinomas (HNSCC).
METHODS: To evaluate the gene hypermethylation profile as a prognostic marker, this retrospective study used a QMSP approach to determine the methylation status of 19 genes in 70 HNSCC patients.
RESULTS: The methylation profile analysis of primary HNSCC revealed that genes CCNA1, DAPK, MGMT, TIMP3 and SFRP1 were frequently hypermethylated, with high specificity and sensitivity. TIMP3 and CCNA1 hypermethylation was significantly associated with lower rates of second primary tumor-free survival (p = 0.007 and p = 0.001; log-rank test, respectively).
CONCLUSION: This study, for the first time, presents CCNA1 and TIMP3 hypermethylation as a helpful tool to identify HNSCC subjects at risk of developing second primary carcinomas.

Li Y, Xu J, Ju H, et al.
A network-based, integrative approach to identify genes with aberrant co-methylation in colorectal cancer.
Mol Biosyst. 2014; 10(2):180-90 [PubMed] Related Publications
Epigenetic changes, including aberrations in DNA methylation, are a common hallmark of many cancers. The identification and interpretation of epigenetic changes associated with cancers may benefit from integration with protein interactomes. Based on the assumption that genes implicated in a specific tumor phenotype will show high aberrant co-methylation patterns with their interacting partners, we propose an integrated approach to uncover cancer-associated genes by integrating a DNA methylome with an interactome. Aberrant co-methylated interactions were first identified in the specific cancer, and genes were then prioritized based on their enrichment in aberrant co-methylation. By applying this to a large-scale colorectal cancer (CRC) dataset, the proposed method increases the power to capture known genes. More importantly, genes possessing high aberrant co-methylation patterns, located at the topological center of the original protein-protein interaction network (PPIN), affect several cancer-associated pathways and form hotspots that are frequently hijacked in cancer. Additionally, the top-ranked candidate genes may also be useful as an indicator of CRC diagnosis and prognosis. Five fold cross-validation of the top-ranked genes in diagnosis reveals that it can achieve an area under the receiver operating characteristic (ROC) curve ranging from 82.2% to 98.4% in three independent datasets. Five of these genes form a core repressive module. CCNA1 and ESR1 in particular are evidently silenced by promoter hypermethylation in CRC cell lines and tissues, whose re-expression markedly suppresses tumor cell survival and clonogenicity. These results show that the network-centric method could identify novel disease biomarkers and model how oncogenic lesions mediate epigenetic changes, providing important insights into tumorigenesis.

Brait M, Maldonado L, Noordhuis MG, et al.
Association of promoter methylation of VGF and PGP9.5 with ovarian cancer progression.
PLoS One. 2013; 8(9):e70878 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To elucidate the role of biological and clinical impact of aberrant promoter hypermethylation (PH) in ovarian cancer (OC).
EXPERIMENTAL DESIGN: PH of PGP9.5, HIC1, AIM1, APC, PAK3, MGMT, KIF1A, CCNA1, ESR1, SSBP2, GSTP1, FKBP4 and VGF were assessed by quantitative methylation specific PCR (QMSP) in a training set. We selected two genes (VGF and PGP9.5) for further QMSP analysis in a larger independent validation (IV) set with available clinical data. Biologic relevance of VGF gene was also evaluated.
RESULTS: PH frequency for PGP9.5 and VGF were 85% (316/372) and 43% (158/366) respectively in the IV set of samples while no PH was observed in controls. In 372 OC cases with available follow up, PGP9.5 and VGF PH were correlated with better patient survival [Hazard Ratios (HR) for overall survival (OS) were 0.59 (95% Confidence Intervals (CI)  = 0.42-0.84, p = 0.004), and 0.73 (95%CI = 0.55-0.97, p = 0.028) respectively, and for disease specific survival (DSS) were 0.57 (95%CI 0.39-0.82, p = 0.003) and 0.72 (95%CI 0.54-0.96, p = 0.027). In multivariate analysis, VGF PH remained an independent prognostic factor for OS (HR 0.61, 95%CI 0.43-0.86, p<0.005) and DSS (HR 0.58, 95%CI 0.41-0.83, p<0.003). Furthermore, PGP9.5 PH was significantly correlated with lower grade, early stage tumors, and with absence of residual disease. Forced expression of VGF in OC cell lines inhibited cell growth.
CONCLUSIONS: Our results indicate that VGF and PGP9.5 PH are potential biomarkers for ovarian carcinoma. Confirmatory cohorts with longitudinal follow-up are required in future studies to define the clinical impact of VGF and PGP9.5 PH before clinical application.

Liu Y, Huang Y, Zhu GZ
Cyclin A1 is a transcriptional target of PITX2 and overexpressed in papillary thyroid carcinoma.
Mol Cell Biochem. 2013; 384(1-2):221-7 [PubMed] Related Publications
Physiological expression of cyclin A1, a unique cell cycle regulator essential for spermatogenesis, is predominantly restricted in male germ cells. Outstandingly, previous studies have also demonstrated the abnormal expression of cyclin A1 in various human tumors. How male germ cell-specific cyclin A1 is transcriptionally activated in tumor cells, however, is elusive. To begin to understand the molecular mechanisms governing the ectopic expression of cyclin A1, we searched for transcription factors and cis-regulatory DNA elements. We found that overexpression of PITX2, a paired-like homeodomain transcription factor and a downstream effector of Wnt/β-catenin signaling, resulted in upregulation of cyclin A1 in HEK293 cells and TPC-1 thyroid cancer cells. On the other hand, PITX2 knockdown in TPC-1 cells caused reduced cyclin A1. Promoter reporter assays with a series of deletion constructs determined that the DNA element from -102 to -96 bp of the cyclin A1 promoter is responsible for PITX2-induced gene expression. The result of chromatin immunoprecipitation revealed the occupancy of PITX2 on the cyclin A1 promoter. Taken together, these findings demonstrate that cyclin A1 is a transcriptional target of PITX2. Consistently, our immunohistochemistry result showed up-regulation of cyclin A1 in human papillary thyroid carcinoma, where overexpressed PITX2 has been endorsed in our recent report. Thus, our study provides new evidence on the regulation of cyclin A1 gene expression and offers a PITX2-cycin A1 pathway for cell cycle regulation.

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