Gene Summary

Gene:GRASP; general receptor for phosphoinositides 1 associated scaffold protein
Aliases: TAMALIN
Summary:This gene encodes a protein that functions as a molecular scaffold, linking receptors, including group 1 metabotropic glutamate receptors, to neuronal proteins. The encoded protein contains conserved domains, including a leucine zipper sequence, PDZ domain and a C-terminal PDZ-binding motif. Alternately spliced transcript variants have been observed for this gene.[provided by RefSeq, Dec 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:general receptor for phosphoinositides 1-associated scaffold protein
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: GRASP (cancer-related)

Bjerre MT, Strand SH, Nørgaard M, et al.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is a clinically heterogeneous disease and currently, accurate diagnostic and prognostic molecular biomarkers are lacking. This study aimed to identify novel DNA hypermethylation markers for PCa with future potential for blood-based testing. Accordingly, to search for genes specifically hypermethylated in PCa tissue samples and not in blood cells or other cancer tissue types, we performed a systematic analysis of genome-wide DNA methylation data (Infinium 450K array) available in the Marmal-aid database for 4072 malignant/normal tissue samples of various types. We identified eight top candidate markers (cg12799885,

Ding Z, Lan H, Xu R, et al.
LncRNA TP73-AS1 accelerates tumor progression in gastric cancer through regulating miR-194-5p/SDAD1 axis.
Pathol Res Pract. 2018; 214(12):1993-1999 [PubMed] Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs) have been considered as significant regulators in many cancer progression, such as proliferation, invasion and other path of evolution. Nevertheless, we have not had a grasp of the role of lncRNA TP73-AS1 in gastric cancer (GC).
METHODS: qRT-PCR analysis was first conducted to examine the TP73-AS1 level in both GC tissues and cell lines. Then gain or loss-of-function assays were carried out to detect the effect of TP73-AS1 on GC development. In mechanism, bioinformatics analysis and luciferase reporter assays were used to search and confirm the target gene of TP73-AS1. Finally, rescue assays were performed to confirm the influence of TP73-AS1-miR-194-5p-SDAD1 axis on GC development.
RESULTS: TP73-AS1 was upregulated in GC tissues and cell lines. Furthermore, TP73-AS1 exerted oncogenic role in GC through promoting cell growth and metastasis. In addition, TP73-AS1 was certified as a ceRNA by regulating miR-194-5p/SDAD1 axis.
CONCLUSIONS: TP73-AS1 accelerates tumor progression in gastric cancer through regulating miR-194-5p/SDAD1 axis.

Erickson KE, Rukhlenko OS, Posner RG, et al.
New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling.
Semin Cancer Biol. 2019; 54:162-173 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
RAS is the most frequently mutated gene across human cancers, but developing inhibitors of mutant RAS has proven to be challenging. Given the difficulties of targeting RAS directly, drugs that impact the other components of pathways where mutant RAS operates may potentially be effective. However, the system-level features, including different localizations of RAS isoforms, competition between downstream effectors, and interlocking feedback and feed-forward loops, must be understood to fully grasp the opportunities and limitations of inhibiting specific targets. Mathematical modeling can help us discern the system-level impacts of these features in normal and cancer cells. New technologies enable the acquisition of experimental data that will facilitate development of realistic models of oncogenic RAS behavior. In light of the wealth of empirical data accumulated over decades of study and the advancement of experimental methods for gathering new data, modelers now have the opportunity to advance progress toward realization of targeted treatment for mutant RAS-driven cancers.

Cardin SE, Borchert GM
Viral MicroRNAs, Host MicroRNAs Regulating Viruses, and Bacterial MicroRNA-Like RNAs.
Methods Mol Biol. 2017; 1617:39-56 [PubMed] Related Publications
As masters of genome-wide regulation, miRNAs represent a key component in the complex architecture of cellular processes. Over the last decade, it has become increasingly apparent that miRNAs have many important roles in the development of disease and cancer. Recently, however, their role in viral and bacterial gene regulation as well as host gene regulation during disease progression has become a field of interest. Due to their small size, miRNAs are the ideal mechanism for bacteria and viruses that have limited room in their genomes, as a single miRNA can target up to ~30 genes. Currently, only a limited number of miRNA and miRNA-like RNAs have been found in bacteria and viruses, a number that is sure to increase rapidly in the future. The interactions of these small noncoding RNAs in such primitive species have wide-reaching effects, from increasing viral and bacterial proliferation, better responses to stress, increased virulence, to manipulation of host immune responses to provide a more ideal environment for these pathogens to thrive. Here, we explore those roles to obtain a better grasp of just how complicated disease truly is.

Barata AT, Santos C, Cravo M, et al.
Handgrip Dynamometry and Patient-Generated Subjective Global Assessment in Patients with Nonresectable Lung Cancer.
Nutr Cancer. 2017; 69(1):154-158 [PubMed] Related Publications
INTRODUCTION: Undernutrition is frequently associated with advanced lung cancer. Accurate nutritional assessment tools are important to provide the proper nutritional therapy. Handgrip dynamometry has already been used in these patients, and the findings suggest that it is a good indicator of nutritional status.
AIMS: The aim of this study was to evaluate the association between nutritional status and handgrip strength (HGS) in patients with nonresectable lung cancer.
METHODS: Cross-sectional study involving thirty-seven subjects with nonresectable lung cancer. Nutritional status was obtained using Patient Generated Subjective Global Assessment (PG-SGA), and muscle function was evaluated by HGS using a Jamar® handgrip dynamometer on the nondominant hand. The results of both methods were compared and correlated.
RESULTS: According to PG-SGA, 73% (n = 27) of the patients were moderately undernourished, and 8% (n = 3) were severely undernourished. In total, 81% (n = 30) were undernourished. HGS was below the 50th percentile in 57% of the patients (n = 21). We found a significant association between nutritional status according to PG-SGA and HGS (P = 0.026, CI = 95%).
CONCLUSIONS: Handgrip dynamometry can be a useful tool to evaluate the functional and nutritional status. It can be included in lung cancer patients evaluation, along with other nutritional assessment tools.

Wood RD, Doublié S
DNA polymerase θ (POLQ), double-strand break repair, and cancer.
DNA Repair (Amst). 2016; 44:22-32 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
DNA polymerase theta (pol θ) is encoded in the genomes of many eukaryotes, though not in fungi. Pol θ is encoded by the POLQ gene in mammalian cells. The C-terminal third of the protein is a family A DNA polymerase with additional insertion elements relative to prokaryotic homologs. The N-terminal third is a helicase-like domain with DNA-dependent ATPase activity. Pol θ is important in the repair of genomic double-strand breaks (DSBs) from many sources. These include breaks formed by ionizing radiation and topoisomerase inhibitors, breaks arising at stalled DNA replication forks, breaks introduced during diversification steps of the mammalian immune system, and DSB induced by CRISPR-Cas9. Pol θ participates in a route of DSB repair termed "alternative end-joining" (altEJ). AltEJ is independent of the DNA binding Ku protein complex and requires DNA end resection. Pol θ is able to mediate joining of two resected 3' ends harboring DNA sequence microhomology. "Signatures" of Pol θ action during altEJ are the frequent utilization of longer microhomologies, and the insertion of additional sequences at joining sites. The mechanism of end-joining employs the ability of Pol θ to tightly grasp a 3' terminus through unique contacts in the active site, allowing extension from minimally paired primers. Pol θ is involved in controlling the frequency of chromosome translocations and preserves genome integrity by limiting large deletions. It may also play a backup role in DNA base excision repair. POLQ is a member of a cluster of similarly upregulated genes that are strongly correlated with poor clinical outcome for breast cancer, ovarian cancer and other cancer types. Inhibition of pol θ is a compelling approach for combination therapy of radiosensitization.

Riwaldt S, Bauer J, Wehland M, et al.
Pathways Regulating Spheroid Formation of Human Follicular Thyroid Cancer Cells under Simulated Microgravity Conditions: A Genetic Approach.
Int J Mol Sci. 2016; 17(4):528 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Microgravity induces three-dimensional (3D) growth in numerous cell types. Despite substantial efforts to clarify the underlying mechanisms for spheroid formation, the precise molecular pathways are still not known. The principal aim of this paper is to compare static 1g-control cells with spheroid forming (MCS) and spheroid non-forming (AD) thyroid cancer cells cultured in the same flask under simulated microgravity conditions. We investigated the morphology and gene expression patterns in human follicular thyroid cancer cells (UCLA RO82-W-1 cell line) after a 24 h-exposure on the Random Positioning Machine (RPM) and focused on 3D growth signaling processes. After 24 h, spheroid formation was observed in RPM-cultures together with alterations in the F-actin cytoskeleton. qPCR indicated more changes in gene expression in MCS than in AD cells. Of the 24 genes analyzed VEGFA, VEGFD, MSN, and MMP3 were upregulated in MCS compared to 1g-controls, whereas ACTB, ACTA2, KRT8, TUBB, EZR, RDX, PRKCA, CAV1, MMP9, PAI1, CTGF, MCP1 were downregulated. A pathway analysis revealed that the upregulated genes code for proteins, which promote 3D growth (angiogenesis) and prevent excessive accumulation of extracellular proteins, while genes coding for structural proteins are downregulated. Pathways regulating the strength/rigidity of cytoskeletal proteins, the amount of extracellular proteins, and 3D growth may be involved in MCS formation.

Yamada N, Yasui K, Dohi O, et al.
Genome-wide DNA methylation analysis in hepatocellular carcinoma.
Oncol Rep. 2016; 35(4):2228-36 [PubMed] Related Publications
Epigenetic changes as well as genetic changes are mechanisms of tumorigenesis. We aimed to identify novel genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We screened for genes with promoter DNA hypermethylation using a genome-wide methylation microarray analysis in primary HCC (the discovery set). The microarray analysis revealed that there were 2,670 CpG sites that significantly differed in regards to the methylation level between the tumor and non-tumor liver tissues; 875 were significantly hypermethylated and 1,795 were significantly hypomethylated in the HCC tumors compared to the non‑tumor tissues. Further analyses using methylation-specific PCR, combined with expression analysis, in the validation set of primary HCC showed that, in addition to three known tumor-suppressor genes (APC, CDKN2A, and GSTP1), eight genes (AKR1B1, GRASP, MAP9, NXPE3, RSPH9, SPINT2, STEAP4, and ZNF154) were significantly hypermethylated and downregulated in the HCC tumors compared to the non-tumor liver tissues. Our results suggest that epigenetic silencing of these genes may be associated with HCC.

Souza T, Jennen D, van Delft J, et al.
New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis.
Arch Toxicol. 2016; 90(6):1449-58 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Benzo(a)pyrene (BaP) is a ubiquitous carcinogen resulting from incomplete combustion of organic compounds and also present at high levels in cigarette smoke. A wide range of biological effects has been attributed to BaP and its genotoxic metabolite BPDE, but the contribution to BaP toxicity of intermediary metabolites generated along the detoxification path remains unknown. Here, we report for the first time how 3-OH-BaP, 9,10-diol and BPDE, three major BaP metabolites, temporally relate to BaP-induced transcriptomic alterations in HepG2 cells. Since BaP is also known to induce AhR activation, we additionally evaluated TCDD to source the expression of non-genotoxic AhR-mediated patterns. 9,10-Diol was shown to activate several transcription factor networks related to BaP metabolism (AhR), oxidative stress (Nrf2) and cell proliferation (HIF-1α, AP-1) in particular at early time points, while BPDE influenced expression of genes involved in cell energetics, DNA repair and apoptotic pathways. Also, in order to grasp the role of BaP and its metabolites in chemical hepatocarcinogenesis, we compared expression patterns from BaP(-metabolites) and TCDD to a signature set of approximately nine thousand gene expressions derived from hepatocellular carcinoma (HCC) patients. While transcriptome modulation by TCDD appeared not significantly related to HCC, BaP and BPDE were shown to deregulate metastatic markers via non-genotoxic and genotoxic mechanisms and activate inflammatory pathways (NF-κβ signaling, cytokine-cytokine receptor interaction). BaP also showed strong repression of genes involved in cholesterol and fatty acid biosynthesis. Altogether, this study provides new insights into BaP-induced toxicity and sheds new light onto its mechanism of action as a hepatocarcinogen.

Shen J, LeFave C, Sirosh I, et al.
Integrative epigenomic and genomic filtering for methylation markers in hepatocellular carcinomas.
BMC Med Genomics. 2015; 8:28 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Epigenome-wide studies in hepatocellular carcinoma (HCC) have identified numerous genes with aberrant DNA methylation. However, methods for triaging functional candidate genes as useful biomarkers for epidemiological study have not yet been developed.
METHODS: We conducted targeted next-generation bisulfite sequencing (bis-seq) to investigate associations of DNA methylation and mRNA expression in HCC. Integrative analyses of epigenetic profiles with DNA copy number analysis were used to pinpoint functional genes regulated mainly by altered DNA methylation.
RESULTS: Significant differences between HCC tumor and adjacent non-tumor tissue were observed for 28 bis-seq amplicons, with methylation differences varying from 12% to 43%. Available mRNA expression data in Oncomine were evaluated. Two candidate genes (GRASP and TSPYL5) were significantly under-expressed in HCC tumors in comparison with precursor and normal liver tissues. The expression levels in tumor tissues were, respectively, 1.828 and - 0.148, significantly lower than those in both precursor and normal liver tissue. Validations in an additional 42 paired tissues showed consistent under-expression in tumor tissue for GRASP (-7.49) and TSPYL5 (-9.71). A highly consistent DNA hypermethylation and mRNA repression pattern was obtained for both GRASP (69%) and TSPYL5 (73%), suggesting that their biological function is regulated by DNA methylation. Another two genes (RGS17 and NR2E1) at Chr6q showed significantly decreased DNA methylation in tumors with loss of DNA copy number compared to those without, suggesting alternative roles of DNA copy number losses and hypermethylation in the regulation of RGS17 and NR2E1.
CONCLUSIONS: These results suggest that integrative analyses of epigenomic and genomic data provide an efficient way to filter functional biomarkers for future epidemiological studies in human cancers.

Klett J, Reeves J, Oberhauser N, et al.
Modulation of toll-like receptor 4. Insights from x-ray crystallography and molecular modeling.
Curr Top Med Chem. 2014; 14(23):2672-83 [PubMed] Related Publications
Toll-like receptors (TLRs) are a family of proteins with a key role in the innate immune system. They are specialized in the recognition of molecular patterns present in microbial components, through mechanisms not yet unraveled at atomic level. Improvement in the understanding of the molecular mechanisms that drive TLR signaling is of paramount importance to grasp key aspects of immunity, potentially leading to the design of new molecules able to modulate their functions. Toll-like receptor 4 (TLR4), along with its accessory protein myeloid differentiation factor 2 (MD-2), builds a heterodimeric complex that specifically recognizes lipopolysaccharides (LPS), which are present on the cell wall of gramnegative bacteria, activating the immune response. Some TLR4 modulators are undergoing preclinical and clinical evaluation for the treatment of sepsis, inflammatory diseases, cancer, and rheumatoid arthritis. Reported X-ray crystal structures together with molecular modeling studies, not reviewed before in the literature, have recently contributed to the elucidation of key interactions at atomic level of the binding between the TLR4/MD-2 system and different TLR4/MD-2 ligands. The purpose of this review is to summarize these reported studies which may account for the SAR rationalization of natural/ synthetic agonist/antagonist TLR4 binders and may also guide further design of novel TLR4 modulators.

Matsumoto Y, Maemondo M, Ishii Y, et al.
A phase II study of erlotinib monotherapy in pre-treated non-small cell lung cancer without EGFR gene mutation who have never/light smoking history: re-evaluation of EGFR gene status (NEJ006/TCOG0903).
Lung Cancer. 2014; 86(2):195-200 [PubMed] Related Publications
OBJECTIVES: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are particularly effective in non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations. However, some studies have reported survival benefits in NSCLC patients with wild-type EGFR upon erlotinib treatment. This trial was conducted to evaluate the efficacy of erlotinib monotherapy and investigate the predictive values of several biomarkers.
PATIENTS AND METHODS: Patients with previously treated NSCLC but without EGFR gene mutations that had never or light smoked were eligible for this study. Gene status screening was performed using the PNA-LNA PCR clamp method. Erlotinib was administered until disease progression or unacceptable toxicities occurred. EGFR gene status was re-evaluated using the fragment method to detect exon 19 deletions and the Cycleave-PCR method to detect point mutations. Expression of hepatocyte growth factor (HGF), Met, and thymidylate synthase (TS) were evaluated using immunohistochemistry.
RESULTS: Forty-seven patients were enrolled in the study between March 2010 and November 2011. Objective response rate (ORR) and disease control rate (DCR) were 15.2% and 41.3%. Re-evaluations for EGFR gene were performed in 32 tumor samples. EGFR gene mutations were found in eight samples (5:exon 19 deletion, 2:G719X, 1:L858R). Six patients had PR and two had SD among these eight patients. A total of 24 patients were confirmed as wild-type EGFR using different methods. ORR and DCR were 4.2% and 41.7%. The median progression free survival (PFS) and median survival times were 2.0 and 6.0 months, respectively. Patients with tumors expressing HGF showed shorter PFS but not MET or TS.
CONCLUSIONS: Re-examination of EGFR gene status using different detecting method or different sample should be considered to grasp a chance of erlotinib treatment after first line treatment. In confirmed EGFR wild NSCLC, negative HGF staining could be a biomarker for longer PFS by erlotonib treatment.

Wang D, Gao G
State-of-the-art human gene therapy: part II. Gene therapy strategies and clinical applications.
Discov Med. 2014; 18(98):151-61 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
In Part I of this Review (Wang and Gao, 2014), we introduced recent advances in gene delivery technologies and explained how they have powered some of the current human gene therapy applications. In Part II, we expand the discussion on gene therapy applications, focusing on some of the most exciting clinical uses. To help readers to grasp the essence and to better organize the diverse applications, we categorize them under four gene therapy strategies: (1) gene replacement therapy for monogenic diseases, (2) gene addition for complex disorders and infectious diseases, (3) gene expression alteration targeting RNA, and (4) gene editing to introduce targeted changes in host genome. Human gene therapy started with the simple idea that replacing a faulty gene with a functional copy can cure a disease. It has been a long and bumpy road to finally translate this seemingly straightforward concept into reality. As many disease mechanisms unraveled, gene therapists have employed a gene addition strategy backed by a deep knowledge of what goes wrong in diseases and how to harness host cellular machinery to battle against diseases. Breakthroughs in other biotechnologies, such as RNA interference and genome editing by chimeric nucleases, have the potential to be integrated into gene therapy. Although clinical trials utilizing these new technologies are currently sparse, these innovations are expected to greatly broaden the scope of gene therapy in the near future.

Giannelli G, Rani B, Dituri F, et al.
Moving towards personalised therapy in patients with hepatocellular carcinoma: the role of the microenvironment.
Gut. 2014; 63(10):1668-76 [PubMed] Related Publications
The goal of personalised therapy based on hepatocellular carcinoma (HCC) molecular characteristics is still beyond our grasp. Systemic treatments show poor efficacy, mainly because of the great heterogeneity of the tumour. Indeed, differences in aetiology, disease stage and biochemical composition of the fibrotic liver make cirrhosis itself a highly dyshomogeneous disease. Cancer cells grow in a cirrhotic microenvironment, interacting with stromal cells and engaging matrix components that differ from patient to patient, hampering the development of drugs to treat all patients. Growing evidence suggests a role for the cross-talk between HCC and the host stroma in driving disease progression and hence prognosis and survival. Many efforts have been devoted to identifying genes responsible for good or bad prognosis, but no study has yet proven helpful in guiding therapeutic choices and management over time, also taking into account the development of drug resistance. The questions of what to target and in which patient are still unsolved. In the personalised therapy scenario, the patient rather than the disease becomes the target of the therapy. However, this still requires an evidence-based medical approach. Herein, we will discuss how individual differences in terms of quality and quantity of the tissue microenvironment components affect progression of HCC. Then, we will highlight potential druggable pathways, also considering ongoing clinical trials. The development of biomarkers will be discussed in the light of new experimental research conducted with the aim of moving towards personalised therapy in patients with HCC.

Santander-Ortega MJ, de la Fuente M, Lozano MV, et al.
Optimisation of synthetic vector systems for cancer gene therapy - the role of the excess of cationic dendrimer under physiological conditions.
Curr Top Med Chem. 2014; 14(9):1172-81 [PubMed] Related Publications
We have previously demonstrated in a therapeutic study that a single systemic course of DAB-Am16 dendriplexes loaded with plasmid expressing TNFα over a period of time of 10 days led to a regression of 100% of tumours and to long term cures of up to 80% of animals. However, the formulation had a relatively low colloidal stability requiring administration soon after nanoparticle preparation. Similar to other cationic polyplex and dendrimer DNA delivery systems, DAB-AM16 dendrimer formulations contained a substantial proportion of free polymer; this free polymer is present independently of the specific polymer:DNA ratio and increases with increasing proportion of polymer (N:P charge ratio) in the formulation. It has previously been shown for this and other systems that the excess of polymer plays a role in promoting the transfection efficiency of synthetic vectors. This has been linked to effects of the polymer on the efficiency of intracellular processing, e.g. endosomal release. However, the free polymer may have additional effects that are relevant to the efficiency of the formulation. This study therefore considered the effect of free dendrimer on the colloidal stability of the complexes, the interaction of the complex with the formulation medium, and with biological components, i.e. electrolytes and serum proteins after administration. Analysis of the total potential of interaction shows that, even at high N:P ratios, the excess of free dendrimer in the medium is not enough to induce the aggregation of the formulation due to depletion forces. This finding is unusual and can be attributed to the particularly low Mw of these dendrimers (1.6 kDa). On the other hand, formulations are highly sensitive to the strength of the dendrimer:DNA interactions. These can be controlled by the degree of protonation (α) of the dendrimer which is strongly dependent on bulk pH. Modulation of the protonation level to α≥0.4 allows reproducible production of colloidally stable particles. Finally, we have demonstrated that electrolytes and proteins present in physiological media play a crucial role to favour the efficiency of these synthetic vectors reducing the toxicity associated with their cationic groups.

Louzoun Y, Xue C, Lesinski GB, Friedman A
A mathematical model for pancreatic cancer growth and treatments.
J Theor Biol. 2014; 351:74-82 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Pancreatic cancer is one of the most deadly types of cancer and has extremely poor prognosis. This malignancy typically induces only limited cellular immune responses, the magnitude of which can increase with the number of encountered cancer cells. On the other hand, pancreatic cancer is highly effective at evading immune responses by inducing polarization of pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages, and promoting expansion of myeloid derived suppressor cells, which block the killing of cancer cells by cytotoxic T cells. These factors allow immune evasion to predominate, promoting metastasis and poor responsiveness to chemotherapies and immunotherapies. In this paper we develop a mathematical model of pancreatic cancer, and use it to qualitatively explain a variety of biomedical and clinical data. The model shows that drugs aimed at suppressing cancer growth are effective only if the immune induced cancer cell death lies within a specific range, that is, the immune system has a specific window of opportunity to effectively suppress cancer under treatment. The model results suggest that tumor growth rate is affected by complex feedback loops between the tumor cells, endothelial cells and the immune response. The relative strength of the different loops determines the cancer growth rate and its response to immunotherapy. The model could serve as a starting point to identify optimal nodes for intervention against pancreatic cancer.

Mitchell SM, Ross JP, Drew HR, et al.
A panel of genes methylated with high frequency in colorectal cancer.
BMC Cancer. 2014; 14:54 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: The development of colorectal cancer (CRC) is accompanied by extensive epigenetic changes, including frequent regional hypermethylation particularly of gene promoter regions. Specific genes, including SEPT9, VIM1 and TMEFF2 become methylated in a high fraction of cancers and diagnostic assays for detection of cancer-derived methylated DNA sequences in blood and/or fecal samples are being developed. There is considerable potential for the development of new DNA methylation biomarkers or panels to improve the sensitivity and specificity of current cancer detection tests.
METHODS: Combined epigenomic methods - activation of gene expression in CRC cell lines following DNA demethylating treatment, and two novel methods of genome-wide methylation assessment - were used to identify candidate genes methylated in a high fraction of CRCs. Multiplexed amplicon sequencing of PCR products from bisulfite-treated DNA of matched CRC and non-neoplastic tissue as well as healthy donor peripheral blood was performed using Roche 454 sequencing. Levels of DNA methylation in colorectal tissues and blood were determined by quantitative methylation specific PCR (qMSP).
RESULTS: Combined analyses identified 42 candidate genes for evaluation as DNA methylation biomarkers. DNA methylation profiles of 24 of these genes were characterised by multiplexed bisulfite-sequencing in ten matched tumor/normal tissue samples; differential methylation in CRC was confirmed for 23 of these genes. qMSP assays were developed for 32 genes, including 15 of the sequenced genes, and used to quantify methylation in tumor, adenoma and non-neoplastic colorectal tissue and from healthy donor peripheral blood. 24 of the 32 genes were methylated in >50% of neoplastic samples, including 11 genes that were methylated in 80% or more CRCs and a similar fraction of adenomas.
CONCLUSIONS: This study has characterised a panel of 23 genes that show elevated DNA methylation in >50% of CRC tissue relative to non-neoplastic tissue. Six of these genes (SOX21, SLC6A15, NPY, GRASP, ST8SIA1 and ZSCAN18) show very low methylation in non-neoplastic colorectal tissue and are candidate biomarkers for stool-based assays, while 11 genes (BCAT1, COL4A2, DLX5, FGF5, FOXF1, FOXI2, GRASP, IKZF1, IRF4, SDC2 and SOX21) have very low methylation in peripheral blood DNA and are suitable for further evaluation as blood-based diagnostic markers.

Cesana D, Ranzani M, Volpin M, et al.
Uncovering and dissecting the genotoxicity of self-inactivating lentiviral vectors in vivo.
Mol Ther. 2014; 22(4):774-85 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Self-inactivating (SIN) lentiviral vectors (LV) have an excellent therapeutic potential as demonstrated in preclinical studies and clinical trials. However, weaker mechanisms of insertional mutagenesis could still pose a significant risk in clinical applications. Taking advantage of novel in vivo genotoxicity assays, we tested a battery of LV constructs, including some with clinically relevant designs, and found that oncogene activation by promoter insertion is the most powerful mechanism of early vector-induced oncogenesis. SIN LVs disabled in their capacity to activate oncogenes by promoter insertion were less genotoxic and induced tumors by enhancer-mediated activation of oncogenes with efficiency that was proportional to the strength of the promoter used. On the other hand, when enhancer activity was reduced by using moderate promoters, oncogenesis by inactivation of tumor suppressor gene was revealed. This mechanism becomes predominant when the enhancer activity of the internal promoter is shielded by the presence of a synthetic chromatin insulator cassette. Our data provide both mechanistic insights and quantitative readouts of vector-mediated genotoxicity, allowing a relative ranking of different vectors according to these features, and inform current and future choices of vector design with increasing biosafety.

Borzekowski DL, Guan Y, Smith KC, et al.
The Angelina effect: immediate reach, grasp, and impact of going public.
Genet Med. 2014; 16(7):516-21 [PubMed] Related Publications
BACKGROUND: In May 2013, Angelina Jolie revealed in a New York Times opinion piece that she had undergone a preventive double mastectomy because she had a family history of cancer and carried a rare mutation of the BRCA1 gene. Media coverage has been extensive, but it is not obvious what messages the public took from this personal health story.
METHODS: We conducted a survey with a representative national online panel of 2,572 adults. Participants described their awareness and identified information sources for the Angelina Jolie news story. They also reported their understanding, reactions, perceptions, and subsequent activities related to the story. We asked questions pertaining to personal and societal breast cancer risk and hypothetical questions regarding preventive surgery if the respondent or a family member were in the same position as Ms Jolie. Demographic information was collected, as was family risk for breast and ovarian cancer, and a gauge of numeracy.
RESULTS: While three of four Americans were aware of Angelina Jolie's double mastectomy, fewer than 10% of respondents had the information necessary to accurately interpret Ms Jolie's risk of developing cancer relative to a woman unaffected by the BRCA gene mutation. Awareness of the Angelina Jolie story was not associated with improved understanding.
CONCLUSION: While celebrities can bring heightened awareness to health issues, there is a need for these messages to be accompanied by more purposeful communication efforts to assist the public in understanding and using the complex diagnostic and treatment information that these stories convey.

You W, Li Z, Jing C, et al.
MTHFR C677T and A1298C polymorphisms were associated with bladder cancer risk and disease progression: a meta-analysis.
DNA Cell Biol. 2013; 32(5):260-7 [PubMed] Related Publications
Epidemiological studies have investigated that functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene may play an essential role in bladder carcinogenesis, but the association between these single-nucleotide polymorphisms in the MTHFR gene and the susceptibility of bladder cancer (BC) was inconsistent in previous studies. The objective of this current study was to conduct an update analysis investigating the association between three polymorphisms in the MTHFR gene and the risk of BC. We performed a meta-analysis of 13 publications involving an association between BC and MTHFR gene three polymorphisms (C677T, A1298C, and G1793A). We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). On one hand, we found that the C677T polymorphism was associated with increased BC risk among Asians, however, with decreased BC risk among a mixed population. Interestingly, BC patients who carried the T-allele (TT+TC) had a higher percentage than the individuals who carried the CC genotype (OR=1.38, 95% CI=1.13-1.69, p=0.002). On the other hand, the A1298C polymorphism may increase BC risk among Asians and Africans, but played a decreased association among Europeans. Results from the current update analysis suggested that the C677T and A1298C polymorphisms in the MTHFR gene were associated with BC risk and disease progression.

Kobayashi Y, Okada Y, Itakura G, et al.
Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity.
PLoS One. 2012; 7(12):e52787 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Murine and human iPSC-NS/PCs (induced pluripotent stem cell-derived neural stem/progenitor cells) promote functional recovery following transplantation into the injured spinal cord in rodents. However, for clinical applicability, it is critical to obtain proof of the concept regarding the efficacy of grafted human iPSC-NS/PCs (hiPSC-NS/PCs) for the repair of spinal cord injury (SCI) in a non-human primate model. This study used a pre-evaluated "safe" hiPSC-NS/PC clone and an adult common marmoset (Callithrix jacchus) model of contusive SCI. SCI was induced at the fifth cervical level (C5), followed by transplantation of hiPSC-NS/PCs at 9 days after injury. Behavioral analyses were performed from the time of the initial injury until 12 weeks after SCI. Grafted hiPSC-NS/PCs survived and differentiated into all three neural lineages. Furthermore, transplantation of hiPSC-NS/PCs enhanced axonal sparing/regrowth and angiogenesis, and prevented the demyelination after SCI compared with that in vehicle control animals. Notably, no tumor formation occurred for at least 12 weeks after transplantation. Quantitative RT-PCR showed that mRNA expression levels of human neurotrophic factors were significantly higher in cultured hiPSC-NS/PCs than in human dermal fibroblasts (hDFs). Finally, behavioral tests showed that hiPSC-NS/PCs promoted functional recovery after SCI in the common marmoset. Taken together, these results indicate that pre-evaluated safe hiPSC-NS/PCs are a potential source of cells for the treatment of SCI in the clinic.

Beggs AD, Jones A, El-Bahrawy M, et al.
Whole-genome methylation analysis of benign and malignant colorectal tumours.
J Pathol. 2013; 229(5):697-704 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Changes in DNA methylation, whether hypo- or hypermethylation, have been shown to be associated with the progression of colorectal cancer. Methylation changes substantially in the progression from normal mucosa to adenoma and to carcinoma. This phenomenon has not been studied extensively and studies have been restricted to individual CpG islands, rather than taking a whole-genome approach. We aimed to study genome-wide methylation changes in colorectal cancer. We obtained 10 fresh-frozen normal tissue-cancer sample pairs, and five fresh-frozen adenoma samples. These were run on the lllumina HumanMethylation27 whole-genome methylation analysis system. Differential methylation between normal tissue, adenoma and carcinoma was analysed using Bayesian regression modelling, gene set enrichment analysis (GSEA) and hierarchical clustering (HC). The highest-rated individual gene for differential methylation in carcinomas versus normal tissue and adenomas versus normal tissue was GRASP (padjusted  = 1.59 × 10(-5) , BF = 12.62, padjusted  = 1.68 × 10(-6) , BF = 14.53). The highest-rated gene when comparing carcinomas versus adenomas was ATM (padjusted  = 2.0 × 10(-4) , BF = 10.17). Hierarchical clustering demonstrated poor clustering by the CIMP criteria for methylation. GSEA demonstrated methylation changes in the Netrin-DCC and SLIT-ROBO pathways. Widespread changes in DNA methylation are seen in the transition from adenoma to carcinoma. The finding that GRASP, which encodes the general receptor for phosphoinositide 1-associated scaffold protein, was differentially methylated in colorectal cancer is interesting. This may be a potential biomarker for colorectal cancer.

Lewitzky M, Simister PC, Feller SM
Beyond 'furballs' and 'dumpling soups' - towards a molecular architecture of signaling complexes and networks.
FEBS Lett. 2012; 586(17):2740-50 [PubMed] Related Publications
The molecular architectures of intracellular signaling networks are largely unknown. Understanding their design principles and mechanisms of processing information is essential to grasp the molecular basis of virtually all biological processes. This is particularly challenging for human pathologies like cancers, as essentially each tumor is a unique disease with vastly deranged signaling networks. However, even in normal cells we know almost nothing. A few 'signalosomes', like the COP9 and the TCR signaling complexes have been described, but detailed structural information on their architectures is largely lacking. Similarly, many growth factor receptors, for example EGF receptor, insulin receptor and c-Met, signal via huge protein complexes built on large platform proteins (Gab, Irs/Dok, p130Cas[BCAR1], Frs families etc.), which are structurally not well understood. Subsequent higher order processing events remain even more enigmatic. We discuss here methods that can be employed to study signaling architectures, and the importance of too often neglected features like macromolecular crowding, intrinsic disorder in proteins and the sophisticated cellular infrastructures, which need to be carefully considered in order to develop a more mature understanding of cellular signal processing.

Ramis-Conde I, Drasdo D
From genotypes to phenotypes: classification of the tumour profiles for different variants of the cadherin adhesion pathway.
Phys Biol. 2012; 9(3):036008 [PubMed] Related Publications
The E-cadherin adhesive profile expressed by a tumour is a characterization of the intracellular and intercellular protein interactions that control cell-cell adhesion. Within the intracellular proteins that determine the tumour adhesive profile, Src and PI3 are two essentials to initiate the formation of the E-cadherin adhesion complex. On the other hand, Src has also the capability of disrupting the β-catenin-E-cadherin complex and down-regulating cell-cell adhesion. In this paper, using a multi-scale mathematical model, we study the role of each of these proteins in the adhesive profile and invasive properties of the tumour. To do this, we create three versions of an intracellular model that explains the interplay between the proteins E-cadherin, β-catenin, Src and PI3; and we couple them to the strength of the cell-cell adhesion forces within an individual-cell-based model. The simulation results show how the tumour profile and its aggressive potential may change depending on the intrinsic characteristics of the protein pathways, and how these pathways may influence the early stages of cancer invasion. Our major findings may be summarized as follows. (1) Intermediate levels of Src synthesis rates generate the least invasive tumour phenotype. (2) Conclusions drawn from findings obtained from the intracellular molecular dynamics (here cadherin-catenin binding complexes) to the multi-cellular invasive potential of a tumour may be misleading or erroneous. The conclusions should be validated in a multi-cellular context on timescales relevant for population growth. (3) Monoclonal populations of more cohesive cells with otherwise equal properties tend to grow slower. (4) Less cohesive cells tend to outcompete more cohesive cells. (5) Less cohesive cells have a larger probability of invasion as migration forces can more easily outbalance cohesive forces.

Kirik U, Cifani P, Albrekt AS, et al.
Multimodel pathway enrichment methods for functional evaluation of expression regulation.
J Proteome Res. 2012; 11(5):2955-67 [PubMed] Related Publications
Functional analysis of quantitative expression data is becoming common practice within the proteomics and transcriptomics fields; however, a gold standard for this type of analysis has yet not emerged. To grasp the systemic changes in biological systems, efficient and robust methods are needed for data analysis following expression regulation experiments. We discuss several conceptual and practical challenges potentially hindering the emergence of such methods and present a novel method, called FEvER, that utilizes two enrichment models in parallel. We also present analysis of three disparate differential expression data sets using our method and compare our results to other established methods. With many useful features such as pathway hierarchy overview, we believe the FEvER method and its software implementation will provide a useful tool for peers in the field of proteomics. Furthermore, we show that the method is also applicable to other types of expression data.

Kim TH, Park YJ, Lim JA, et al.
The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.
Cancer. 2012; 118(7):1764-73 [PubMed] Related Publications
BACKGROUND: The effects of the BRAF(V600E) mutation on prognostic factors and poor clinical outcomes in papillary thyroid cancer (PTC) have not been fully quantified. The authors performed comprehensive meta-analysis to assess the strength of associations between these conditions and the BRAF(V600E) mutation.
METHODS: The authors identified the clinical studies that examined the association of the BRAF(V600E) mutation in surgical specimens with clinicopathologic outcomes between January 2003 and October 2010 using the Medline database. One hundred thirty-one relevant studies were hand-searched. The authors selected 27 studies that included 5655 PTC patients. They calculated the pooled odds ratios (ORs) or risk ratios with 95% confidence intervals (CIs) for each study using a random effect model.
RESULTS: The average prevalence rate of the BRAF(V600E) mutation was 49.4%. In 26 studies, compared with the patients who had the wild-type BRAF genes, the PTC patients with the BRAF(V600E) mutation had increased ORs of an extrathyroidal invasion (OR, 2.14; 95% CI, 1.68-2.73), a lymph node metastasis (OR, 1.54; 95% CI, 1.21-1.97), and an advanced TNM stage (OR, 2.00; 95% CI, 1.61-2.49). In 8 studies, patients with the mutation had 2.14-fold increased risk of recurrent and persistent disease (95% CI, 1.67-2.74). The associations were generally consistent across the different study populations.
CONCLUSIONS: This meta-analysis demonstrates that the BRAF(V600E) mutation is closely related to the high-risk clinicopathological factors and poorer outcome of PTC. The results obtained here suggest that the BRAF(V600E) mutation should be considered as a poor prognostic marker in PTC and may lead to better management for individual patients.

Tao R, Li J, Xin J, et al.
Methylation profile of single hepatocytes derived from hepatitis B virus-related hepatocellular carcinoma.
PLoS One. 2011; 6(5):e19862 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: With the development of high-throughput screening, a variety of genetic alterations has been found in hepatocellular carcinoma (HCC). Although previous studies on HCC methylation profiles have focused on liver tissue, studies using isolated hepatocytes are rare. The heterogeneity of liver composition may impact the genuine methylation status of HCC; therefore, it is important to clarify the methylation profile of hepatocytes to aid in understanding the process of tumorigenesis.
METHODS AND FINDINGS: The global methylation profile of single hepatocytes isolated from liver tissue of hepatitis B virus (HBV) related HCC (HBHC) was analyzed using Illumina Infinium Human Methylation27 BeadChips, and combined bisulfite restriction analysis (COBRA) and bisulfite sequencing were used to validate the 20 significant hypermethylated genes identified. In this study, we found many noteworthy differences in the genome-wide methylation profiles of single hepatocytes of HBHC. Unsupervised hierarchical clustering analysis showed that hepatocyte methylation profiles could be classified according to three cell types: hepatocytes of HCC, adjacent hepatocytes and normal hepatocytes. Among the 20 most hypermethylated genes in the hepatocytes of HBHC, 7 novel genes (WNK2, EMILIN2, TLX3, TM6SF1, TRIM58, HIST1H4Fand GRASP) were found to be hypermethylated in HBHC and hypomethylated in paired adjacent liver tissues; these findings have not been reported in previous studies on tissue samples.
CONCLUSION: The genome-wide methylation profile of purified single hepatocytes of HBHC was aided in understanding the process of tumorigenesis, and a series of novel methylated genes found in this study have the potential to be biomarkers for the diagnosis and prognosis of HBHC.

James TW, Frias-Staheli N, Bacik JP, et al.
Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease.
Proc Natl Acad Sci U S A. 2011; 108(6):2222-7 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
The attachment of ubiquitin (Ub) and the Ub-like (Ubl) molecule interferon-stimulated gene 15 (ISG15) to cellular proteins mediates important innate antiviral responses. Ovarian tumor (OTU) domain proteases from nairoviruses and arteriviruses were recently found to remove these molecules from host proteins, which inhibits Ub and ISG15-dependent antiviral pathways. This contrasts with the Ub-specific activity of known eukaryotic OTU-domain proteases. Here we describe crystal structures of a viral OTU domain from the highly pathogenic Crimean-Congo haemorrhagic fever virus (CCHFV) bound to Ub and to ISG15 at 2.5-Å and 2.3-Å resolution, respectively. The complexes provide a unique structural example of ISG15 bound to another protein and reveal the molecular mechanism of an ISG15 cross-reactive deubiquitinase. To accommodate structural differences between Ub and ISG15, the viral protease binds the β-grasp folds of Ub and C-terminal Ub-like domain of ISG15 in an orientation that is rotated nearly 75° with respect to that observed for Ub bound to a representative eukaryotic OTU domain from yeast. Distinct structural determinants necessary for binding either substrate were identified and allowed the reengineering of the viral OTU protease into enzymes with increased substrate specificity, either for Ub or for ISG15. Our findings now provide the basis to determine in vivo the relative contributions of deubiquitination and deISGylation to viral immune evasion tactics, and a structural template of a promiscuous deubiquitinase from a haemorrhagic fever virus that can be targeted for inhibition using small-molecule-based strategies.

Hoque MO
DNA methylation changes in prostate cancer: current developments and future clinical implementation.
Expert Rev Mol Diagn. 2009; 9(3):243-57 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Promoter hypermethylation is associated with the loss of expression of tumor-suppressor genes in cancer. Currently, several genome-wide technologies are available and have been utilized to examine the extent of DNA methylation in discovery-based studies involving several physiological and disease states. Although early in the process, aberrant DNA methylation is gaining strength in the fields of cancer risk assessment, diagnosis and therapy monitoring in different cancer types. There is a need to improve existing methods for early diagnosis of prostate cancer and to identify men at risk for developing aggressive disease. Because of the ubiquity of DNA methylation changes and the ability to detect methylated DNA in several body fluids (e.g., blood and urine), this specifically altered DNA may serve, on one hand, as a possible new screening marker for prostate cancer and, on the other hand, as a tool for therapy monitoring in patients having had neoplastic disease of the prostate. Since many prostate cancer patients present with advanced disease and some present with nonspecific elevation of prostate-specific antigen without prostate cancer, early detection with high specificity and sensitivity is considered to be one of the most important approaches to reduce mortality and unwanted tension of the men with high prostate-specific antigen. Therefore, an effective screening test would have substantial clinical benefits. Furthermore, methylation markers of risk of progression of disease in patients having prostate cancer permits immediate commencement of specific treatment regimens and probably longer survival and better quality of life. This review illustrates the current benefits and limitations of potentially useful prostate cancer methylation markers that have considerable existing data and touches upon other future markers as well as the field of methylation in prostate cancer.

Wunderlich M, Mulloy JC
Model systems for examining effects of leukemia-associated oncogenes in primary human CD34+ cells via retroviral transduction.
Methods Mol Biol. 2009; 538:263-85 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
The use of primary human cells to model cancer initiation and progression is now within the grasp of investigators. It has been nearly a decade since the first defined genetic elements were introduced into primary human epithelial and fibroblast cells to model oncogenesis. This approach has now been extended to the hematopoietic system, with the first described experimental transformation of primary human hematopoietic cells. Human cell model systems will lead to a better understanding of the species and cell type specific signals necessary for oncogenic initiation and progression, and will allow investigators to interrogate the cancer stem cell hypothesis using a well-defined hierarchical system that has been studied for decades. The molecular and biochemical link between self-renewal and differentiation can now be experimentally approached using primary human cells. In addition, the models that result from these experiments are likely to generate highly relevant systems for use in identification and validation of potential therapeutic targets as well as testing of small molecule therapeutics. We describe here the methodologies and reagents that are used to examine the effects of leukemia fusion protein expression on primary human hematopoietic cells, both in vitro and in vivo.

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