GRASP

Gene Summary

Gene:GRASP; GRP1 (general receptor for phosphoinositides 1)-associated scaffold protein
Aliases: TAMALIN
Location:12q13.13
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, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:general receptor for phosphoinositides 1-associated scaffold protein
HPRD
Source:NCBIAccessed: 27 August, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 27 August, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: GRASP (cancer-related)

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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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] Free Access to Full Article 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.

Griffith GL, Edwards RT, Williams JM, et al.
Patient preferences and National Health Service costs: a cost-consequences analysis of cancer genetic services.
Fam Cancer. 2009; 8(4):265-75 [PubMed] Related Publications
The study has three aims; firstly to establish if, having been informed of their risk status and that gene testing is inappropriate for them, low and moderate risk patients have misunderstood or failed to grasp this and want a test that is inappropriate for them. Secondly, to elicit patients' willingness to pay for cancer genetic services. Thirdly, to ascertain the aspects of cancer genetics services that are important to high risk patients and present service configurations prioritised in terms of preferences accompanied by their costs (cost-consequences analysis). Patient preferences were gathered from 120 patients returning a self-administered discrete choice questionnaire issued post genetic risk assessment. Patients at low and moderate risk of developing breast cancer desired inappropriate testing. Patients at high, moderate and low risk of developing genetic cancer were willing to pay up to 3,000 pounds for genetic serviced, which exceeds the current estimated cost of providing testing and counselling. Counselling by a genetics associate accompanied by favourable levels of other attributes provided high utility and substantial cost savings.

Kotiligam D, Lazar AJ, Pollock RE, Lev D
Desmoid tumor: a disease opportune for molecular insights.
Histol Histopathol. 2008; 23(1):117-26 [PubMed] Related Publications
Desmoid tumors are monoclonal proliferations that fall within a broad histologic spectrum of fibrous mesenchymal tumors that ranges from benign proliferations of scar tissue to high-grade fibrosarcomas. These low-grade tumors are extremely infiltrative locally, but lack the ability to metastasize systemically. While they are only rarely a direct cause of mortality, using current therapeutic modalities, these tumors have a high rate of local recurrence that can result in significant treatment related morbidity. Sporadic desmoids are usually associated with somatic mutations in codons 41 or 45 of exon 3 of beta-catenin (CTNNB1). Desmoid tumors occurring in the background of familial adenomatous polyposis (FAP) usually contain inactivating germline mutations in the adenomatous polyposis coli (APC) gene. CTNNB1 and APC are part of the Wnt signaling pathway and mutations in either gene result in stabilization of the beta-catenin protein and allow nuclear translocation and binding of beta-catenin to the T-cell factor/lymphoid enhancer factor (TCF/Lef) family of transcription factors, resulting in activation of target genes which may underlie desmoid tumor biology and clinical behavior. In an era of molecularly targeted therapeutics there is a real need to better grasp the molecular mechanisms behind desmoid tumorigenesis and progression. This knowledge will eventually result in the development of patient and tumor tailored therapies and assist in the control and eradication of this disease.

Lubitz RJ, Komaromy M, Crawford B, et al.
Development and pilot evaluation of novel genetic educational materials designed for an underserved patient population.
Genet Test. 2007; 11(3):276-90 [PubMed] Related Publications
Genetic counseling for BRCA1 and BRCA2 mutations involves teaching about hereditary cancer, genetics and risk, subjects that are difficult to grasp and are routinely misunderstood. Supported by a grant from the Avon Foundation, the UCSF Cancer Risk Program started the first genetic testing and counseling service for a population of traditionally underserved women of varied ethnic and social backgrounds at the San Francisco General Hospital (SFGH). Informed by educational theory and clinical experience, we devised and piloted two simplified explanations of heredity and genetic risk, with the aim of uncovering how to best communicate genetics and risk to this underserved population. A "conventional" version comprised pictures of genes, pedigrees, and quantitative representations of risk. A "colloquial" pictorial version used an analogy of the "information book" of genes, family stories and vignettes, and visual representations of risk, without using scientific words such as genes or chromosomes. A verbal narrative accompanied each picture. We presented these modules to four focus groups of five to eight women recruited from the SFGH Family Practice Clinic. Overall, women preferred a picture-based approach and commented that additional text would have been distracting. The majority of women preferred the colloquial version because it was easier to understand and better conveyed a sense of comfort and hope. We conclude that simplicity, analogies, and familiarity support comprehension while vignettes, family stories, and photos of real people provide comfort and hope. These elements may promote understanding of complex scientific topics in healthcare, particularly when communicating with patients who come from disadvantaged backgrounds.

Wang Y, Giel-Moloney M, Rindi G, Leiter AB
Enteroendocrine precursors differentiate independently of Wnt and form serotonin expressing adenomas in response to active beta-catenin.
Proc Natl Acad Sci U S A. 2007; 104(27):11328-33 [PubMed] Free Access to Full Article Related Publications
Wnt signaling is required for the maintenance of intestinal stem cells and self-renewal of the intestinal epithelium. Intestinal cancers are frequently associated with mutations that activate the Wnt pathway. The role of Wnt signaling on differentiation of lineage-specific precursors in the intestine is not well characterized. Here, we show that specification of enteroendocrine but not Paneth cells occurs independently of Wnt signals by conditional deletion of beta-catenin in immature cells expressing the transcription factor, neurogenin 3. In addition, we determined whether neurogenin 3-expressing cells respond to abnormal Wnt signaling. Activation of the Wnt pathway by conditionally deleting exon 3 of the beta-catenin gene at an early stage of enteroendocrine cell differentiation induced small-intestinal adenomas expressing serotonin, a feature not previously described in other tumors induced by Wnt in mice. In contrast, excision of exon 3 of beta-catenin at a later stage of enteroendocrine differentiation did not produce tumors. These results provide direct evidence that some intestinal lineages are specified independently of the Wnt pathway and may lead to a better understanding of the spectrum of neuroendocrine differentiation frequently seen in human gastrointestinal cancer.

Tarin D
New insights into the pathogenesis of breast cancer metastasis.
Breast Dis. 2006-2007; 26:13-25 [PubMed] Related Publications
Synthesis and integration of macroscopic and microscopic findings on the pathogenesis of breast cancer and metastasis with recent cellular and molecular research on these topics provides a modern re-evaluation of the disease, which is relevant to clinical efforts and further research. At a microscopic level, tumors are not merely aggregates of malignant cells but are maladjusted living entities, which recruit host stromal cells such as fibroblasts, endothelial cells, etc. with which they intermingle and interact. The result is the formation of an expanding, distorted but recognizable caricature of the histology of the organ from which they are derived, which destroys adjacent normal tissue. The acquisition of metastatic capability endows the tumor with unique powers to parasitize other organs of the living host, with which it shares near complete genetic identity. This exceptional situation renders the parasitic cells almost invisible to host defences and poses a grave threat to host survival. The disseminated cancer cells present to the host defences very much the same problem that a guerilla army presents to orthodox military forces, because the disorderly tumor cells are difficult to distinguish from normal ones and are distributed in small units, in a large terrain. Recent evidence of disturbed molecular interactions between the colonizing and host populations offers the idea that one might be able to deploy classical counter-insurgency concepts based upon the dual approach, firstly of denying support from the indigenous population, by using drugs and secondly, of infiltrating the cells from within, using targeted genetic vectors. Both of these therapeutic approaches are not yet within our grasp, but we have recognized the nature of the adversary and will eventually be able to design tools to undermine its drive and progress.

Shai RM
Microarray tools for deciphering complex diseases.
Front Biosci. 2006; 11:1414-24 [PubMed] Related Publications
Individual genetic findings associated with complex diseases are unlikely to fully explain their substantial impact or provide new comprehensive insights into disease pathogenesis. These also lack the comprehensive data much needed for development of new effective drugs in majority of the disease cases in a population. In fact multilevel etiologic factors underlie almost all human diseases, including: environmental causes, epigenetic factors, DNA mutations, amplifications, and deletions, RNA expression levels, protein (translation, post translation modification, localization) and combinations thereof. Each individual might consist of different combinations of these multiple etiologic factors. Integrative evaluation of all these modifications will shed light on the whole identity of the disease and the underlying molecular mechanisms. Until now it was inconceivable to have a full grasp of such a complex etiology. Microarrays enable us to interrogate the individualized various factors (DNA, RNA and protein content) involved in disease state on genome-wide scale simultaneously and expeditiously in single cell or the tissue of interest (Figure 1). The new disciplines of microarray studies in combination hold the promise of effective, current, and comprehensive understanding of complex diseases and may be a good approach for reducing the costs and time lines associated with discovery and efficacy improvement of therapeutic drugs. In the future, through utilizing the colossal amount of microarray data findings, defining the structure, function, and dynamics of entire biological pathways and cellular networks under various physiological states, and the development of robust and efficient methods for analyzing and interpreting high dimensional data, it will be possible to connect combination of experimental results with individualized disease state. This will facilitate precise diagnosis prognosis and therapy.

Zhou X, Mao KZ
LS Bound based gene selection for DNA microarray data.
Bioinformatics. 2005; 21(8):1559-64 [PubMed] Related Publications
MOTIVATION: One problem with discriminant analysis of DNA microarray data is that each sample is represented by quite a large number of genes, and many of them are irrelevant, insignificant or redundant to the discriminant problem at hand. Methods for selecting important genes are, therefore, of much significance in microarray data analysis. In the present study, a new criterion, called LS Bound measure, is proposed to address the gene selection problem. The LS Bound measure is derived from leave-one-out procedure of LS-SVMs (least squares support vector machines), and as the upper bound for leave-one-out classification results it reflects to some extent the generalization performance of gene subsets.
RESULTS: We applied this LS Bound measure for gene selection on two benchmark microarray datasets: colon cancer and leukemia. We also compared the LS Bound measure with other evaluation criteria, including the well-known Fisher's ratio and Mahalanobis class separability measure, and other published gene selection algorithms, including Weighting factor and SVM Recursive Feature Elimination. The strength of the LS Bound measure is that it provides gene subsets leading to more accurate classification results than the filter method while its computational complexity is at the level of the filter method.
AVAILABILITY: A companion website can be accessed at http://www.ntu.edu.sg/home5/pg02776030/lsbound/. The website contains: (1) the source code of the gene selection algorithm; (2) the complete set of tables and figures regarding the experimental study; (3) proof of the inequality (9).
CONTACT: ekzmao@ntu.edu.sg.

von Eschenbach AC
A vision for the National Cancer Program in the United States.
Nat Rev Cancer. 2004; 4(10):820-8 [PubMed] Related Publications
The intersection of two noble endeavors - the scientists' quest to understand life itself and the physicians' dedication to relieve suffering and prolong life - came into sharp focus in 1971 with the United States National Cancer Act. This focus has led to an exponential expansion of our understanding of cancer at the genetic, molecular and cellular levels, and concomitant advances in our ability to disrupt the disease process through prevention, early detection and successful treatment. At the National Cancer Institute we are committed to capitalize on these achievements. A new era is now within our grasp, a time when no one suffers or dies as a result of cancer.

Sohda M, Ishikawa H, Masuda N, et al.
Pretreatment evaluation of combined HIF-1alpha, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer.
Int J Cancer. 2004; 110(6):838-44 [PubMed] Related Publications
Tumor hypoxia has been known to be associated with resistance to radiation and chemotherapy (CRT). Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor induced by hypoxic condition, plays a major role in the pleiotropic response observed under hypoxic conditions. It encodes proteins that play key roles in critical development and physiologic processes, including angiogenesis, glucose transport and erythropoiesis. On the other hand, cell cycle- and apoptosis-control genes p53 and p21 may play major roles in the tumor response to cytotoxic agents such as radiation and chemotherapy. Previous reports have suggested that the regulation of p53 and p21 is HIF-1-dependent. Our aim was to evaluate the expression of the HIF-1alpha, p53 and p21 proteins by immunohistochemistry in biopsy specimens of esophageal squamous cell carcinoma, which were obtained endoscopically from 65 patients before CRT, and then determine whether the levels of expression of these proteins predicted the clinical effectiveness of CRT in individual cancers. Also, to assess the relationship between expression of these proteins and cell death and cellular proliferation activity, we evaluated Ki67 expression and the apoptosis index (TUNEL). HIF-1alpha expression in esophageal cancer was significantly and negatively related to the response to CRT, independently of p53 and p21 expression. Interestingly, 44.4% (12/27) of the HIF-1alpha-negative group showed a complete response to therapy. There was no significant correlation between the expression of HIF-1alpha, p53 and p21 and proliferation and apoptosis. HIF-1alpha overexpression may predict resistance to CRT and may be a helpful guide in choosing between therapeutic strategies, such as intensive combined modality therapy vs. palliative therapy. Combined immunohistochemical evaluation of HIF-1alpha, p53 and p21 protein expression at the pretreatment biopsy is a very useful and powerful indicator of sensitivity to CRT in human esophageal cancer. Our data also indicate the importance of having a clear grasp of the degree of hypoxia (HIF-1alpha) of a tumor, rather than its cellular character (proliferation and apoptosis), to indicate the likely impact of CRT.

Tsai SF, Chen PJ
Impact of human genome research on medicine--the initial Taiwan experience.
J Formos Med Assoc. 2000; 99(2):107-15 [PubMed] Related Publications
The human genome contains at least 80,000 genes, and each carries out its unique biologic function in the human body. Gene mutation and variation may result in hereditary disease, cancer, hypertension, and even susceptibility to infectious diseases. A complete compilation of all human genes (the human genome) should allow a better understanding of the role of specific genes in diseases and, consequently, better design of effective treatments. The human genome project (HGP) is scheduled to be completed in 2003. This article reviews the novel technology used in the HGP and the new information that will be generated. The results will influence medical practice greatly. Indeed, as in the forthcoming era of genomic medicine, a battery of gene tests is likely to be as routine as blood chemistry tests are today. The impacts are to be felt soon and medical professionals should be ready to grasp and apply new knowledge as it becomes available to better serve their patients. We also describe how the findings from the HGP might be used to solve locally important medical problems, using the examples of genomic research in liver and nasopharyngeal cancers. Finally, because the HGP has raised many new ethical, legal, and social challenges that should often take precedence over the problems of technology, an overview of these issues is also provided.

Shillitoe EJ, Noonan S
Strength and specificity of different gene promoters in oral cancer cells.
Oral Oncol. 2000; 36(2):214-20 [PubMed] Related Publications
Gene therapy of oral cancer will require expression of genes by promoters that are both powerful and relatively tumor specific. We compared the level of expression of a reporter gene from promoters of human cytomegalovirus (CMV), SV40 virus, mouse mammary tumor virus (MMTV), human papillomaviruses (HPV) types 16 and 18, and the human multi-drug-resistance gene (mdr1), in several lines of oral cancer cells. In the oral cancer cell line 686LN the rank order of expression levels was: CMV > SV40 > HPV > mdr1 > MMTV. Unlike in previous reports the mdr1 promoter was no more active in two cancer cell lines with mutations in the p53 gene than in two other lines with wild-type p53, and its expression level could not be increased by either doxorubicin or taxol. On the other hand, expression from the MMTV promoter was increased over 10-fold by the presence of 1 microM dexamethasone. Thus, by an appropriate choice of promoter and inducer a wide variety of expression levels, over a 3-log range, could be attained in 686LN cells. The oral cancer-specificity of each promoter was judged by comparing expression in the neuroblastoma line IMR32. The most specific promoters were those from papillomaviruses, which were up to 45 times more active in the oral cancer cells, and the least specific was the CMV promoter. In order to find if an HPV-derived promoter was sufficient to produce expression of a suicide phenotype the 686 promoter was cloned adjacent to the thymidine kinase gene of herpes simplex and the construct was expressed from an adenovirus vector. The vector reduced the growth of 686LN cells over a 5-day period by up to 32% when optimal concentrations of virus and ganciclovir were used. These data will be valuable in the design of new constructs for gene therapy of oral cancer.

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