Research IndicatorsGraph generated 15 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TES (cancer-related)
BACKGROUND: Childhood acute lymphoblastic leukaemia (ALL) is the most common malignancy in children. Despite high cure rates, side effects and late consequences of the intensive treatments are common. Unquestionably, the identification of new therapeutic targets will lead to safer, more effective treatments. We identified TES promoter methylation and transcriptional silencing as a very common molecular abnormality in childhood ALL, irrespective of molecular subtype. The aims of the present study were to demonstrate that TES promoter methylation is aberrant, to determine the effects of TES re-expression in ALL, and to determine if those effects are mediated via TP53 activity.
METHODS: Normal fetal and adult tissue DNA was isolated and TES promoter methylation determined by Sequenom MassARRAY. Quantitative RT-PCR and immunoblot were used to confirm re-expression of TES in ALL cell lines after 5'-aza-2'-deoxycytidine (decitabine) exposure or transfection with TES expression plasmids. The effects of TES re-expression on ALL cells were investigated using standard cell proliferation, cell death and cell cycle assays.
RESULTS: In this study, we confirm that the TES promoter is unmethylated in normal adult and fetal tissues. We report that decitabine treatment of ALL cell lines results in demethylation of the TES promoter and attendant expression of TES mRNA. Re-expression of TESTIN protein in ALL cells using expression plasmid transfection results in rapid cell death or cell cycle arrest independent of TP53 activity.
CONCLUSIONS: These results suggest that TES is aberrantly methylated in ALL and that re-expression of TESTIN has anti-leukaemia effects which point to novel therapeutic opportunities for childhood ALL.
Aberrant DNA methylation at promoters is often linked to tumorigenesis. But many aspects of DNA methylation remain unexplored, including the individual roles of distal and gene body methylation, as well as their collaborative roles with promoter methylation. Here we performed a MBD-seq analysis on prostate specimens classified into low, high, and very high risk group based on Gleason score and TNM stages. We identified gene sets with differential methylation regions (DMRs) in Distal, TSS, gene body and TES. To understand the collaborative roles, TSS was compared with the other three DMRs, resulted in 12 groups of genes with collaborative differential methylation patterns (CDMPs). We found several groups of genes that show opposite methylation patterns in Distal and Genic regions compared to TSS region, and in general they are differentially expressed genes (DEGs) in tumors in TCGA RNA-seq data. IPA (Ingenuity Pathway Analysis) reveals AR/TP53 signaling network to be a major signaling pathway, and survival analysis indicates genes subsets significantly associated with prostate cancer recurrence. Our results suggest that DNA methylation in Distal and Genic regions also plays critical roles in contributing to prostate tumorigenesis, and may act either positively or negatively with TSSs to alter gene regulation in tumors.
Cancer/testis (CT) antigens are normally expressed in testis and overexpressed in various tumor types. However, their biological function is largely unknown. OY-TES-1, one of cancer/testis (CT) antigens, is reported overexpression in hepatocellular carcinoma (HCC). And we assumed that OY-TES-1 contribute to oncogenesis and progression of HCC. In this study, we knocked down OY-TES-1 by small interference RNA (siRNA) in HCC cell lines (HepG2 and BEL-7404) to verify this assumption and evaluate its potential as therapeutic targets for HCC. We showed that down regulation of OY-TES-1 decreased cell growth, induced the G0/G1 arrest and apoptosis, and prevented migration and invasion in the two HCC cell lines. Further analysis revealed that down regulation of OY-TES-1 increased expression of apoptosis-regulated protein caspase-3, and decreased expression of cell cycle-regulated protein cyclin E, migration/invasion-regulated proteins MMP2 and MMP9. These findings may shed light on the gene therapy about the OY-TES-1 expression in HCC cells.
Zhong Z, Zhang F, Yin SCEffects of TESTIN gene expression on proliferation and migration of the 5-8F nasopharyngeal carcinoma cell line.
Asian Pac J Cancer Prev. 2015; 16(6):2555-9 [PubMed
] Related Publications
PURPOSE: To investigate effects of the TESTIN (TES) gene on proliferation and migration of highly metastatic nasopharyngeal carcinoma cell line 5-8F and the related mechanisms.
MATERIALS AND METHODS: The target gene of human nasopharyngeal carcinoma cell line 5-8F was amplified by PCR and cloned into the empty plasmid pEGFP-N1 to construct a eukaryotic expression vector pEGFP-N1-TES. This was then transfected into 5-8F cells. MTT assays, flow cytometry and scratch wound tests were used to detect the proliferation and migration of transfected 5-8F cells.
RESULTS: A cell model with stable and high expression of TES gene was successfully established. MTT assays showed that the OD value of 5-8F/TES cells was markedly lower than that of 5-8F/GFP cells and 5-8F cells (p<0.05). Flow cytometry showed that the apoptosis rate of 5-8F/TES cells was prominently increased compared with 5-8F/GFP cells and 5-8F cells (p<0.05). In vitro scratch wound assays showed that, the width of the wound area of 5-8F/TES cells narrowed slightly, while the width of the wound area of 5-8F/ GFP cells and 5-8F cells narrowed sharply, suggesting that the TES overexpression could inhibit the migration ability.
CONCLUSIONS: TES gene expression remarkably inhibits the proliferation of human nasopharyngeal carcinoma cell line 5-8F and reduces its migration in vitro. Thus, it may be a potential tumor suppressor gene for nasopharyngeal carcinoma.
BACKGROUND: African American (AA) women are diagnosed with more advanced breast cancers and have worse survival than white women, but a comprehensive understanding of the basis for this disparity remains unclear. Analysis of DNA methylation, an epigenetic mechanism that can regulate gene expression, could help to explain racial differences in breast tumor clinical biology and outcomes.
METHODS: DNA methylation was evaluated at 1,287 CpGs in the promoters of cancer-related genes in 517 breast tumors of AA (n = 216) or non-AA (n = 301) cases in the Carolina Breast Cancer Study (CBCS).
RESULTS: Multivariable linear regression analysis of all tumors, controlling for age, menopausal status, stage, intrinsic subtype, and multiple comparisons [false discovery rate (FDR)], identified seven CpG probes that showed significant (adjusted P < 0.05) differential methylation between AAs and non-AAs. Stratified analyses detected an additional four CpG probes differing by race within hormone receptor-negative (HR(-)) tumors. Genes differentially methylated by race included DSC2, KCNK4, GSTM1, AXL, DNAJC15, HBII-52, TUSC3, and TES; the methylation state of several of these genes may be associated with worse survival in AAs. TCGA breast tumor data confirmed the differential methylation by race and negative correlations with expression for most of these genes. Several loci also showed racial differences in methylation in peripheral blood leukocytes (PBL) from CBCS cases, indicating that these variations were not necessarily tumor-specific.
CONCLUSIONS: Racial differences in the methylation of cancer-related genes are detectable in both tumors and PBLs from breast cancer cases.
IMPACT: Epigenetic variation could contribute to differences in breast tumor development and outcomes between AAs and non-AAs.
Chenais BTransposable elements in cancer and other human diseases.
Curr Cancer Drug Targets. 2015; 15(3):227-42 [PubMed
] Related Publications
Transposable elements (TEs) are mobile DNA sequences representing a substantial fraction of most genomes. Through the creation of new genes and functions, TEs are important elements of genome plasticity and evolution. However TE insertion in human genomes may be the cause of genetic dysfunction and alteration of gene expression contributing to cancer and other human diseases. Besides the chromosome rearrangements induced by TE repeats, this mini-review shows how gene expression may be altered following TE insertion, for example by the creation of new polyadenylation sites, by the creation of new exons (exonization), by exon skipping and by other modification of alternative splicing, and also by the alteration of regulatory sequences. Through the correlation between TE mobility and the methylation status of DNA, the importance of chromatin regulation is evident in several diseases. Finally this overview ends with a brief presentation of the use of TEs as biotechnology tools for insertional mutagenesis screening and gene therapy with DNA transposons.
Dong R, Pu H, Wang Y, et al.TESTIN was commonly hypermethylated and involved in the epithelial-mesenchymal transition of endometrial cancer.
APMIS. 2015; 123(5):394-400 [PubMed
] Related Publications
We previously reported frequent loss of TESTIN in human endometrial carcinoma, which significantly suppressed tumor proliferation and invasion. Herein, we further explored the mechanisms underlying TESTIN loss and its roles in the epithelial-mesenchymal transition (EMT, a key step for tumor spreading). Methylation-specific PCR was performed to investigate the promoter status of TESTIN in a panel of endometrial cancer and normal endometrium tissues. The expression of TESTIN mRNA was determined by real-time PCR. Up- and down-regulation of TESTIN were achieved by transient transfection with pcDNA3.1-TESTIN and shRNA-TESTIN plasmids, respectively. The EMT alterations were observed under the optical microscope and EMT-related markers were detected by real-time PCR and western blot. Compared to the control (3.6%), TESTIN was hypermethylated in 43.7% endometrial cancer tissues (p < 0.001). Moreover, TESTIN hypermethylation was significantly correlated with advanced tumor stage, deep myometrial invasion and lymphatic node metastasis. In vitro, the demethylating agent dramatically restored the expression of TESTIN. In addition, up-regulation of TESTIN significantly suppressed the EMT procedure; whereas down-regulation of TESTIN enhanced EMT. In conclusion, we demonstrated that loss of TESTIN was mainly caused by hypermethylation, which might be a potent prognostic marker. Furthermore, we proved that TESTIN significantly suppressed the EMT procedure, proposing restoration of TESTIN to be a novel therapeutic strategy for endometrial carcinoma.
Hu Q, Fu J, Luo B, et al.OY-TES-1 may regulate the malignant behavior of liver cancer via NANOG, CD9, CCND2 and CDCA3: a bioinformatic analysis combine with RNAi and oligonucleotide microarray.
Oncol Rep. 2015; 33(4):1965-75 [PubMed
] Related Publications
Given its tumor-specific expression, including liver cancer, OY-TES-1 is a potential molecular marker for the diagnosis and immunotherapy of liver cancers. However, investigations of the mechanisms and the role of OY-TES-1 in liver cancer are rare. In the present study, based on a comprehensive bioinformatic analysis combined with RNA interference (RNAi) and oligonucleotide microarray, we report for the first time that downregulation of OY-TES-1 resulted in significant changes in expression of NANOG, CD9, CCND2 and CDCA3 in the liver cancer cell line BEL-7404. NANOG, CD9, CCND2 and CDCA3 may be involved in cell proliferation, migration, invasion and apoptosis, yet also may be functionally related to each other and OY-TES-1. Among these molecules, we identified that NANOG, containing a Kazal-2 binding motif and homeobox, may be the most likely candidate protein interacting with OY-TES-1 in liver cancer. Thus, the present study may provide important information for further investigation of the roles of OY-TES-1 in liver cancer.
PIWI-interacting RNAs (piRNAs) have long been associated with the silencing of transposable elements (TEs). However, over 20,000 unique species of piRNAs mapped to the human genome are more than the relatively few presumably required to regulate the known human transposon classes. Here, we present the results of the first genome-wide effort to study the effects of piRNAs on gene specific DNA methylation. We found that exon-derived piRNAs consist almost universally of species with 10 or fewer genomic copies, whereas piRNAs existing in high copies originate predominately from intronic and intergenic regions. Genome-wide methylation profiling following transfection of human somatic cells with piRNA mimics revealed methylation changes at numerous genic loci in single copy piRNA-transfected cells. Moreover, genomic regions directly adjacent to differentially methylated CpG sites were enriched for sequence matches to the transfected piRNAs. These findings suggest that a subset of single copy piRNAs may be able to induce DNA methylation at non-TE genic loci, a process that may be mediated in part by direct binding to either genomic DNA or nascent mRNA near target CpG sites.
BACKGROUND: Gliomas are the most common human brain tumors. Glioblastoma, also known as glioblastoma multiform (GBM), is the most aggressive, malignant, and lethal glioma. The investigation of prognostic and diagnostic molecular biomarkers in glioma patients to provide direction on clinical practice is urgent. Recent studies demonstrated that abnormal DNA methylation states play a key role in the pathogenesis of this kind of tumor. In this study, we want to identify a novel biomarker related to glioma initiation and find the role of the glioma-related gene.
METHODS: We performed a methylation-specific microarray on the promoter region to identify methylation gene(s) that may affect outcome of GBM patients. Normal and GBM tissues were collected from Tiantan Hospital. Genomic DNA was extracted from these tissues and analyzed with a DNA promoter methylation microarray. Testis derived transcript (TES) protein expression was analyzed by immunohistochemistry in paraffin-embedded patient tissues. Western blotting was used to detect TES protein expression in the GBM cell line U251 with or without 5-aza-dC treatment. Cell apoptosis was evaluated by flow cytometry analysis using Annexin V/PI staining.
RESULTS: We found that the TES promoter was hypermethylated in GBM compared to normal brain tissues under DNA promoter methylation microarray analysis. The GBM patients with TES hypermethylation had a short overall survival (P <0.05, log-rank test). Among GBM samples, reduced TES protein level was detected in 33 (89.2%) of 37 tumor tissues by immunohistochemical staining. Down regulation of TES was also correlated with worse patient outcome (P <0.05, log-rank test). Treatment on the GBM cell line U251 with 5-aza-dC can greatly increase TES expression, confirming the hypermethylation of TES promoter in GBM. Up-regulation of TES prompts U251 apoptosis significantly. This study demonstrated that both TES promoter hypermethylation and down-regulated protein expression significantly correlated with worse patient outcome. Treatment on the GBM cell line (U251) with 5-aza-dC can highly release TES expression resulting in significant apoptosis in these cells.
CONCLUSIONS: Our findings suggest that the TES gene is a novel tumor suppressor gene and might represent a valuable prognostic marker for glioblastoma, indicating a potential target for future GBM therapy.
BACKGROUND: Aberrant DNA methylation is a hallmark of many cancers. Classically there are two types of endometrial cancer, endometrioid adenocarcinoma (EAC), or Type I, and uterine papillary serous carcinoma (UPSC), or Type II. However, the whole genome DNA methylation changes in these two classical types of endometrial cancer is still unknown.
RESULTS: Here we described complete genome-wide DNA methylome maps of EAC, UPSC, and normal endometrium by applying a combined strategy of methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme digestion sequencing (MRE-seq). We discovered distinct genome-wide DNA methylation patterns in EAC and UPSC: 27,009 and 15,676 recurrent differentially methylated regions (DMRs) were identified respectively, compared with normal endometrium. Over 80% of DMRs were in intergenic and intronic regions. The majority of these DMRs were not interrogated on the commonly used Infinium 450K array platform. Large-scale demethylation of chromosome X was detected in UPSC, accompanied by decreased XIST expression. Importantly, we discovered that the majority of the DMRs harbored promoter or enhancer functions and are specifically associated with genes related to uterine development and disease. Among these, abnormal methylation of transposable elements (TEs) may provide a novel mechanism to deregulate normal endometrium-specific enhancers derived from specific TEs.
CONCLUSIONS: DNA methylation changes are an important signature of endometrial cancer and regulate gene expression by affecting not only proximal promoters but also distal enhancers.
Naveira H, Bello X, Abal-Fabeiro JL, Maside XEvidence for the persistence of an active endogenous retrovirus (ERVE) in humans.
Genetica. 2014; 142(5):451-60 [PubMed
] Related Publications
Transposable elements (TEs) account for nearly half (44 %) of the human genome. However, their overall activity has been steadily declining over the past 35-50 million years, so that <0.05 % of TEs are presumably still "alive" (potentially transposable) in human populations. All the active elements are retrotransposons, either autonomous (LINE-1 and possibly the endogenous retrovirus ERVK), or non-autonomous (Alu and SVA, whose transposition is dependent on the LINE-1 enzymatic machinery). Here we show that a lineage of the endogenous retrovirus ERVE was recently engaged in ectopic recombination events and may have at least one potentially fully functional representative, initially reported as a novel retrovirus isolated from blood cells of a Chinese patient with chronic myeloid leukemia, which bears signals of positive selection on its envelope region. Altogether, there is strong evidence that ERVE should be included in the short list of potentially active TEs, and we give clues on how to identify human specific insertions of this element that are likely to be segregating in some of our populations.
Yongbin Y, Jinghua L, Zhanxue Z, et al.TES was epigenetically silenced and suppressed the epithelial-mesenchymal transition in breast cancer.
Tumour Biol. 2014; 35(11):11381-9 [PubMed
] Related Publications
The TES gene was frequently lost in breast cancer, which could inhibit tumor invasion and the formation of distant metastasis. However, the underlying mechanisms remain unknown yet. In the present study, we aimed to investigate how TES was silenced and its roles in EMT--the key step for tumor metastasis. Real-time polymerase chain reaction (PCR) and Western blot were used to detect the mRNA and protein expression of target genes; the status of TES promoter was determined by methylation-specific PCR and subsequently, DNA sequencing. Overexpression or downregulation of TES was achieved by pcDNA3.1-TES or shRNA-TES transfection. Cellular adhesion and migration were investigated by the adhesion and Transwell assays. Morphological changes of breast cancer cells were observed under the optical microscope. The Rho A activity was measured using a commercial kit, and its roles in TES-manipulated EMT were determined by real-time PCR and Western blot. The 42.3% (33/78) breast cancer tissues presented hypermethylation of the TES gene, whereas only 2 (2.6%) non-malignant cases were hypermethylated (P<0.001). Moreover, TES hypermethylation was significantly correlated with larger tumor diameter (P=0.03) and lympho node metastasis (P=0.024). In primary cultured breast cancer cells, the demethylation treatment using 5-aza-dC notably restored the expression of TES. In vitro, overexpression of TES enhanced cellular adhesion inhibited migration and suppressed EMT, while downregulation of TES impaired cellular adhesion, promoted migration, and enhanced EMT. TES overexpression also activated the Rho A signal, which is a critical factor for the effects of TES on the EMT procedure. We firstly proved that frequent loss of TES in breast cancer was caused by promoter hypermethylation, which was correlated with poor prognosis. In vitro, TES enhanced cellular adhesion, suppressed tumor migration, and inhibited EMT. Moreover, the Rho A pathway was critical for the effects of TES on EMT, which can be blocked by the Rho A inhibitor. Therefore, we propose restoration of TES as a potent strategy for breast cancer therapy.
Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences harbor multiple regulatory motifs and hence are capable of influencing expression of host genes. In response to environmental changes, TEs are known to be released from epigenetic repression and to become transcriptionally active. Such activation could also lead to lineage-inappropriate activation of oncogenes, as one study described in Hodgkin lymphoma. However, little further evidence for this mechanism in other cancers has been reported. Here, we reanalyzed whole transcriptome data from a large cohort of patients with diffuse large B-cell lymphoma (DLBCL) compared with normal B-cell centroblasts to detect genes ectopically expressed through activation of TE promoters. We have identified 98 such TE-gene chimeric transcripts that were exclusively expressed in primary DLBCL cases and confirmed several in DLBCL-derived cell lines. We further characterized a TE-gene chimeric transcript involving a fatty acid-binding protein gene (LTR2-FABP7), normally expressed in brain, that was ectopically expressed in a subset of DLBCL patients through the use of an endogenous retroviral LTR promoter of the LTR2 family. The LTR2-FABP7 chimeric transcript encodes a novel chimeric isoform of the protein with characteristics distinct from native FABP7. In vitro studies reveal a dependency for DLBCL cell line proliferation and growth on LTR2-FABP7 chimeric protein expression. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in cancer and suggest that LTR2-FABP7 may contribute to the pathogenesis of DLBCL in a subgroup of patients.
BACKGROUND: The TESTIN gene was demonstrated to be a tumor suppressor in prostate and breast cancer through inhibiting tumor growth and invasion. Herein, we aimed to investigate the detailed functions of TESTIN in the highly sexual hormone (estrogen)-dependent malignancy, endometrial carcinoma.
MATERIAL AND METHODS: TESTIN mRNA and protein expression were measured by qRT-PCR, Western blot and immunohistochemistry. Upregulation of TESTIN was achieved by transfecting the pcDNA3.1-TESTIN plasmids into AN3CA cells. Knockdown of TESTIN was achieved by transfecting the shRNA-TESTIN into Ishikawa cells. MTT assay, colony formation assay, and Transwell assay were used to investigate the effects of TESTIN on cellular proliferation and invasion. The apoptotic status and cell cycle were analyzed using flow cytometry. MMP2 secretion was determined by ELISA assay. The xenograft assay was used to investigate the functions of TESTIN in nude mice.
RESULTS: Compared to the non-malignant adjacent endometrium, 54% of tumor samples presented downregulation of TESTIN (P<0.001). Loss of TESTIN protein was correlated with advanced tumor stage (P=0.047), high grade (P=0.034), and lymphatic vascular space invasion (P=0.036). In vitro, overexpression of TESTIN suppressed cell proliferation, induced dramatic G1 arrest, and inhibited tumor invasion through blocking the secretion of MMP2. Loss of TESTIN accelerated cellular proliferation, promoted cell cycle progression, and enhanced tumor invasion by increasing the secretion of MMP2. Consistently, TESTIN could significantly delay the growth of xenografts in nude mice.
CONCLUSIONS: TESTIN was commonly downregulated in human endometrial carcinoma and was associated with poor prognostic markers. Moreover, TESTIN signiﬁcantly inhibited tumor growth and invasion via arresting cell cycle in in vitro and in vivo experiments. Therefore, we propose that TESTIN might be a prognostic marker and therapeutic target for endometrial carcinoma.
BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is a rare WHO grade II tumor accounting for less than 1% of all astrocytomas. Malignant transformation into PXA with anaplastic features, is unusual and correlates with poorer outcome of the patients.
METHODS: Using a DNA methylation custom array, we have quantified the DNA methylation level on the promoter sequence of 807 cancer-related genes of WHO grade II (n = 11) and III PXA (n = 2) and compared to normal brain tissue (n = 10) and glioblastoma (n = 87) samples. DNA methylation levels were further confirmed on independent samples by pyrosequencing of the promoter sequences.
RESULTS: Increasing DNA promoter hypermethylation events were observed in anaplastic PXA as compared with grade II samples. We further validated differential hypermethylation of CD81, HCK, HOXA5, ASCL2 and TES on anaplastic PXA and grade II tumors. Moreover, these epigenetic alterations overlap those described in glioblastoma patients, suggesting common mechanisms of tumorigenesis.
CONCLUSIONS: Even taking into consideration the small size of our patient populations, our data strongly suggest that epigenome-wide profiling of PXA is a valuable tool to identify methylated genes, which may play a role in the malignant progression of PXA. These methylation alterations may provide useful biomarkers for decision-making in those patients with low-grade PXA displaying a high risk of malignant transformation.
Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.
Sato K, Siomi MCPiwi-interacting RNAs: biological functions and biogenesis.
Essays Biochem. 2013; 54:39-52 [PubMed
] Related Publications
The integrity of the germline genome must be maintained to achieve successive generations of a species, because germline cells are the only source for transmitting genetic information to the next generation. Accordingly, the germline has acquired a system dedicated to protecting the genome from 'injuries' caused by harmful selfish nucleic acid elements, such as TEs (transposable elements). Accumulating evidence shows that a germline-specific subclass of small non-coding RNAs, piRNAs (piwi-interacting RNAs), are necessary for silencing TEs to protect the genome in germline cells. To silence TEs post-transcriptionally and/or transcriptionally, mature piRNAs are loaded on to germline-specific Argonaute proteins, or PIWI proteins, to form the piRISC (piRNA-induced silencing complex). The present chapter will highlight insights into the molecular mechanisms underlying piRISC-mediated silencing and piRNA biogenesis, and discuss a possible link with tumorigenesis, particularly in Drosophila.
Wang LJ, Bai Y, Bao ZS, et al.Hypermethylation of testis derived transcript gene promoter significantly correlates with worse outcomes in glioblastoma patients.
Chin Med J (Engl). 2013; 126(11):2062-6 [PubMed
] Related Publications
BACKGROUND: Glioblastoma is the most common and lethal cancer of the central nervous system. Global genomic hypomethylation and some CpG island hypermethylation are common hallmarks of these malignancies, but the effects of these methylation abnormalities on glioblastomas are still largely unclear. Methylation of the O6-methylguanine-DNA methyltransferase promoter is currently an only confirmed molecular predictor of better outcome in temozolomide treatment. To better understand the relationship between CpG island methylation status and patient outcome, this study launched DNA methylation profiles for thirty-three primary glioblastomas (pGBMs) and nine secondary glioblastomas (sGBMs) with the expectation to identify valuable prognostic and therapeutic targets.
METHODS: We evaluated the methylation status of testis derived transcript (TES) gene promoter by microarray analysis of glioblastomas and the prognostic value for TES methylation in the clinical outcome of pGBM patients. Significance analysis of microarrays was used for genes significantly differently methylated between 33 pGBM and nine sGBM. Survival curves were calculated according to the Kaplan-Meier method, and differences between curves were assessed using the log-rank test. Then, we treated glioblastoma cell lines (U87 and U251) with 5-aza-2-deoxycytidines (5-aza-dC) and detected cell biological behaviors.
RESULTS: Microarray data analysis identified TES promoter was hypermethylated in pGBMs compared with sGBMs (P < 0.05). Survival curves from the Kaplan-Meier method analysis revealed that the patients with TES hypermethylation had a short overall survival (P < 0.05). This abnormality is also confirmed in glioblastoma cell lines (U87 and U251). Treating these cells with 5-aza-dC released TES protein expression resulted in significant inhibition of cell growth (P = 0.013).
CONCLUSIONS: Hypermethylation of TES gene promoter highly correlated with worse outcome in pGBM patients. TES might represent a valuable prognostic marker for glioblastoma.
Sarti M, Pinton S, Limoni C, et al.Differential expression of testin and survivin in breast cancer subtypes.
Oncol Rep. 2013; 30(2):824-32 [PubMed
] Related Publications
Testin (TES) is a putative tumour-suppressor gene downregulated in various types of cancers. Survivin is a nodal protein involved in multiple signalling pathways, tumour maintenance and inhibition of apoptosis. Previous studies indicate that TES and survivin can functionally interact and modulate cell death and proliferation in breast cancer cells. The aim of the present study was to investigate the expression and prognostic relevance of TES and survivin in breast cancer subtypes examining a large cohort of breast cancer patients. We determined the expression of TES and survivin by immunohistochemistry (IHC) in tissue samples from 242 breast cancer patients diagnosed between 1981 and 2009. The expression of these proteins was compared with clinical and pathological data. There was a significant association of nuclear survivin overexpression and TES downregulation with triple-negative tumours [P=0.009; univariate odds ratio (OR), 3.20; 95% CI, 1.34-7.66] (P=0.018; multivariate OR, 2.90; 95% CI, 1.20‑6.97). A further significant correlation was observed between TES downregulation and the luminal B subtype (P=0.019, univariate OR: 2.90; 95% CI, 1.19‑7.06) (P=0.032, multivariate OR, 2.67; 95% CI, 1.09-6.65), independent of survivin expression. Our results demonstrated a statistically significant association between TES downregulation and highly aggressive breast tumour subtypes, such as triple-negative and luminal B tumours, along with the prognostic relevance of nuclear expression of survivin. To our knowledge, this is the first demonstration of such an association.
Reuven B, Margarita I, Dov H, Ziad KMultiple trichoepitheliomas associated with a novel heterozygous mutation in the CYLD gene as an adjunct to the histopathological diagnosis.
Am J Dermatopathol. 2013; 35(4):445-7 [PubMed
] Related Publications
Multiple trichoepitheliomas (TEs), especially in the familial setting, have been associated with germline heterozygous mutations in the CYLD gene. Heterozygous germline CYLD mutations and loss of heterozygosity of the CYLD gene in the TE tumor cells have been recently demonstrated in some of the multiple TE cases irrespective of a family history. The histopathological differential diagnosis of TE from basal cell carcinoma may be difficult especially in cases with multiple TEs. Immunohistochemical markers may be used, although some with conflicting results. We describe a 35-year-old woman with multiple facial TEs, in whom the molecular genetic analysis revealed a novel heterozygous c.1843delT mutation in the CYLD gene. This frameshift mutation was also present in a heterozygous state in the TE tumor cells. The demonstration of a novel CYLD mutation was used as an adjunct to the histopathological diagnosis in this case.
Skiriutė D, Vaitkienė P, Ašmonienė V, et al.Promoter methylation of AREG, HOXA11, hMLH1, NDRG2, NPTX2 and Tes genes in glioblastoma.
J Neurooncol. 2013; 113(3):441-9 [PubMed
] Related Publications
Epigenetic alterations alone or in combination with genetic mechanisms play a key role in brain tumorigenesis. Glioblastoma is one of the most common, lethal and poor clinical outcome primary brain tumors with extraordinarily miscellaneous epigenetic alterations profile. The aim of this study was to investigate new potential prognostic epigenetic markers such as AREG, HOXA11, hMLH1, NDRG2, NTPX2 and Tes genes promoter methylation, frequency and value for patients outcome. We examined the promoter methylation status using methylation-specific polymerase chain reaction in 100 glioblastoma tissue samples. The value for clinical outcome was calculated using Kaplan-Meier estimation with log-rank test. DNA promoter methylation was frequent event appearing more than 45 % for gene. AREG and HOXA11 methylation status was significantly associated with patient age. HOXA11 showed the tendency to be associated with patient outcome in glioblastomas. AREG gene promoter methylation showed significant correlation with poor patient outcome. AREG methylation remained significantly associated with patient survival in a Cox multivariate model including MGMT promoter methylation status. This study of new epigenetic targets has shown considerably high level of analyzed genes promoter methylation variability in glioblastoma tissue. AREG gene might be valuable marker for glioblastoma patient survival prognosis, however further analysis is needed to clarify the independence and appropriateness of the marker.
Neumann F, Kaddu-Mulindwa D, Widmann T, et al.EBV-transformed lymphoblastoid cell lines as vaccines against cancer testis antigen-positive tumors.
Cancer Immunol Immunother. 2013; 62(7):1211-22 [PubMed
] Related Publications
EBV-transformed lymphoblastoid cell lines (LCL) are potent antigen-presenting cells. To investigate their potential use as cancer testis antigen (CTA) vaccines, we studied the expression of 12 cancer testis (CT) genes in 20 LCL by RT-PCR. The most frequently expressed CT genes were SSX4 (50 %), followed by GAGE (45 %), SSX1 (40 %), MAGE-A3 and SSX2 (25 %), SCP1, HOM-TES-85, MAGE-C1, and MAGE-C2 (15 %). NY-ESO-1 and MAGE-A4 were found in 1/20 LCL and BORIS was not detected at all. Fifteen of 20 LCL expressed at least one antigen, 9 LCL expressed ≥2 CT genes, and 7 of the 20 LCL expressed ≥4 CT genes. The expression of CT genes did not correlate with the length of in vitro culture, telomerase activity, aneuploidy, or proliferation state. While spontaneous expression of CT genes determined by real-time PCR and Western blot was rather weak in most LCL, treatment with DNA methyltransferase 1 inhibitor alone or in combination with histone deacetylase inhibitors increased CTA expression considerably thus enabling LCL to induce CTA-specific T cell responses. The stability of the CT gene expression over prolonged culture periods makes LCL attractive candidates for CT vaccines both in hematological neoplasias and solid tumors.
Kim YJ, Jung YD, Kim TO, Kim HSAlu-related transcript of TJP2 gene as a marker for colorectal cancer.
Gene. 2013; 524(2):268-74 [PubMed
] Related Publications
Identifying diagnostic markers is very important in cancer biology. Transposable elements (TEs) account for 45% of the human genome and are usually silent in normal tissues. Contrary to this, in cancer tissues, TEs have been found to be expressed specifically with genomic instability. Here, we investigated the transcripts related to TEs using bioinformatic tools and RT-PCR analysis in tumor and adjacent normal tissues as well as in cancer cell lines. From this analysis, we identified the Alu-related transcript of TJP2 gene (TJP2-Alu transcript) that was differentially expressed between tumor and normal tissues. Its expression was higher in colon cancer cell lines and tumor tissues of colorectal cancer patients. These results could contribute to a better understanding of the involvement of TEs in human colorectal cancer, and to evaluating their potential as diagnostic markers for colorectal cancer.
Stricker SH, Feber A, Engström PG, et al.Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner.
Genes Dev. 2013; 27(6):654-69 [PubMed
] Free Access to Full Article Related Publications
Epigenetic changes are frequently observed in cancer. However, their role in establishing or sustaining the malignant state has been difficult to determine due to the lack of experimental tools that enable resetting of epigenetic abnormalities. To address this, we applied induced pluripotent stem cell (iPSC) reprogramming techniques to invoke widespread epigenetic resetting of glioblastoma (GBM)-derived neural stem (GNS) cells. GBM iPSCs (GiPSCs) were subsequently redifferentiated to the neural lineage to assess the impact of cancer-specific epigenetic abnormalities on tumorigenicity. GiPSCs and their differentiating derivatives display widespread resetting of common GBM-associated changes, such as DNA hypermethylation of promoter regions of the cell motility regulator TES (testis-derived transcript), the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C; p57KIP2), and many polycomb-repressive complex 2 (PRC2) target genes (e.g., SFRP2). Surprisingly, despite such global epigenetic reconfiguration, GiPSC-derived neural progenitors remained highly malignant upon xenotransplantation. Only when GiPSCs were directed to nonneural cell types did we observe sustained expression of reactivated tumor suppressors and reduced infiltrative behavior. These data suggest that imposing an epigenome associated with an alternative developmental lineage can suppress malignant behavior. However, in the context of the neural lineage, widespread resetting of GBM-associated epigenetic abnormalities is not sufficient to override the cancer genome.
Sellheyer K, Cribier B, Nelson P, et al.Basaloid tumors in nevus sebaceus revisited: the follicular stem cell marker PHLDA1 (TDAG51) indicates that most are basal cell carcinomas and not trichoblastomas.
J Cutan Pathol. 2013; 40(5):455-62 [PubMed
] Related Publications
BACKGROUND: Until the 1990s, basal cell carcinoma (BCC) was viewed as the most common epithelial neoplasm developing in association with nevus sebaceus (NS). Currently, trichoblastoma is thought of as the most prevalent basaloid neoplasm in NS. The follicular stem cell marker pleckstrin homology-like domain, family A, member 1 (PHLDA1) also known as T-cell death-associated gene 51 (TDAG51) labels trichoepithelioma (TE) but not BCC. Therefore, we explored its usefulness in basaloid neoplasms developing in NS.
METHODS: We studied immunohistochemically PHLDA1 in 10 nodular BCCs, 11 TEs, 11 trichoblastomas and 25 NS with basaloid tumors. Additionally, we examined the expression of BCC marker BerEP4 and the distribution of Merkel cells that function as surrogate markers for benign follicular neoplasms.
RESULTS: Nineteen of the 25 basaloid tumors in NS were PHLDA1-negative comparable to BCC arising de novo and six tumors were PHLDA1-positive comparable to solitary trichoblastomas and TEs. Fewer Merkel cells were seen in BCCs associated with NS when compared with trichoblastoma. BerEP4 did not discriminate between the neoplasms.
CONCLUSIONS: We raise concern that the unquestioned assessment that basaloid tumors developing in association with NS represent mostly trichoblastomas and not BCC may not be true. This influences clinical care, as it is paramount in the decision of whether to excise these lesions or not.
Akagi K, Li J, Symer DEHow do mammalian transposons induce genetic variation? A conceptual framework: the age, structure, allele frequency, and genome context of transposable elements may define their wide-ranging biological impacts.
Bioessays. 2013; 35(4):397-407 [PubMed
] Free Access to Full Article Related Publications
In this essay, we discuss new insights into the wide-ranging impacts of mammalian transposable elements (TE) on gene expression and function. Nearly half of each mammalian genome is comprised of these mobile, repetitive elements. While most TEs are ancient relics, certain classes can move from one chromosomal location to another even now. Indeed, striking recent data show that extensive transposition occurs not only in the germline over evolutionary time, but also in developing somatic tissues and particular human cancers. While occasional germline TE insertions may contribute to genetic variation, many other, similar TEs appear to have little or no impact on neighboring genes. However, the effects of somatic insertions on gene expression and function remain almost completely unknown. We present a conceptual framework to understand how the ages, allele frequencies, molecular structures, and especially the genomic context of mammalian TEs each can influence their various possible functional consequences.
Zhu J, Li X, Kong X, et al.Testin is a tumor suppressor and prognostic marker in breast cancer.
Cancer Sci. 2012; 103(12):2092-101 [PubMed
] Related Publications
The testin (TES) gene was previously identified in the fragile chromosomal region FRA7G at 7q31.2. In the present study, we aimed to investigate the candidate tumor suppressor function of TES and explore its correlations to clinicopathologic features and prognosis in breast cancer. In clinical samples, we showed that the expression of TES decreased gradually from normal through ductal hyperplasia without atypia, atypical ductal hyperplasia, and ductal carcinoma in situ, to invasive ductal carcinoma. To explore the possible tumor suppressing function of TES, the expression of TES in breast cancer cells was manipulated by ectopic expression or by RNAi. We revealed that ectopic TES expression significantly inhibited cell proliferation, invasive ability, and angiogenesis, whereas knockdown of TES by RNAi enhanced cell proliferation, invasive ability, and angiogenesis. In an animal model, TES markedly inhibited breast cancer cell xenograft formation in athymic nude mice and reduced breast cancer cell metastasis to lung. Moreover, we revealed that TES inhibited the invasion and angiogenesis of breast cancer partially through miR-29b-mediated MMP-2 inhibition. Using the tissue microarray of breast cancer from Yale University, we found that lower TES expression was an independent prognostic factor for shorter overall survival and disease-free survival with univariate and multivariate analyses. Taken together, these data suggest that TES, as a valuable marker of breast cancer prognosis, plays an important role in the development and progression of breast cancer. TES may be an effective novel target in breast cancer prevention and treatment.
Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis.
Vizkeleti L, Ecsedi S, Rakosy Z, et al.Prognostic relevance of the expressions of CAV1 and TES genes on 7q31 in melanoma.
Front Biosci (Elite Ed). 2012; 4:1802-12 [PubMed
] Related Publications
The 7q31 locus contains several genes affected in cancer progression. Although evidences exist regarding its impact on tumorigenesis, the role of genetic alterations and the expressions of locus-related genes are still controversial. Our study aimed to define the 7q31 copy number alterations in primary melanomas, primary-metastatic tumor pairs and cell lines. Data were correlated with clinical-pathological parameters. Genetic data show that 7q31 copy number distribution was heterogeneous in both primary and metastatic tumors. Extra copies were highly accompanied by chromosome 7 polisomy, and significantly increased in primary lesions with poor prognosis. Additionally, we determined the mRNA and protein levels of the locus-related CAV1 and TES genes. TES mRNA level was associated with metastatic location. CAV1 mRNA and protein levels were significantly higher in thicker tumors, however, lack of protein was also observed in a subpopulation of thin lesions. Expressions of CAV1 and TES were not associated with 7q31 alterations. In conclusion, 7q31 amplification can predict unfavorable outcome. Alterations of TES mRNA level may predict the location of metastasis. CAV1 possibly affect the cancer cell invasion.