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AP-2α Induces Epigenetic Silencing of Tumor Suppressive Genes and Microsatellite Instability in Head and Neck Squamous Cell Carcinoma
Kristi L. Bennett, Todd Romigh, Charis Eng
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006931
Abstract: Background Activator protein 2 alpha (AP-2α) is involved in a variety of physiological processes. Increased AP-2α expression correlates with progression in various squamous cell carcinomas, and a recent publication found AP-2α to be overexpressed in ~70% of Head and Neck Squamous Cell Carcinoma (HNSCC) patient samples. It was found to repress transcription of the tumor suppressor gene C/CAAT Enhancer Binding Protein alpha (C/EBPα), and its binding site correlated with upstream methylation of the C/EBPα promoter. Therefore, we investigated the potential for AP-2α to target methylation to additional genes that would be relevant to HNSCC pathogenesis. Principal Findings Stable downregulation of AP-2α stable by shRNA in HNSCC cell lines correlated with decreased methylation of its target genes' regulatory regions. Furthermore, methylation of MLH1 in HNSCC with and without AP-2α downregulation revealed a correlation with microsatellite instability (MSI). ChIP analysis was used to confirm binding of AP-2α and HDAC1/2 to the targets. The effects of HDAC inhibition was assessed using Trichostatin A in a HNSCC cell line, which revealed that AP-2α targets methylation through HDAC recruitment. Conclusions These findings are significant because they suggest AP-2α plays a role not only in epigenetic silencing, but also in genomic instability. This intensifies the potential level of regulation AP-2α has through transcriptional regulation. Furthermore, these findings have the potential to revolutionize the field of HNSCC therapy, and more generally the field of epigenetic therapy, by targeting a single gene that is involved in the malignant transformation via disrupting DNA repair and cell cycle control.
Microenvironmental genomic alterations reveal signaling networks for head and neck squamous cell carcinoma
Gurkan Bebek, Mohammed Orloff, Charis Eng
Journal of Clinical Bioinformatics , 2011, DOI: 10.1186/2043-9113-1-21
Abstract: Under the assumption that genes in proximity to identified LOH/AI regions are correlated with the tumorigenic phenotype, we mined publicly available biological information to identify pathway segments (signaling proteins connected to each other in a network) and identify the role of tumor microenvironment in HNSCC. Across both neoplastic epithelial cells and the surrounding stromal cells, genetic alterations in HNSCC were successfully identified, and 75 markers were observed to have significantly different LOH/AI frequencies in these compartments (p < 0.026). We applied a network identification approach to the genes in proximity to these 75 markers in cancer epithelium and stroma in order to identify biological networks that can describe functional associations amongst these marker-associated genes.We verified the involvement of T-cell receptor signaling pathways in HNSCC as well as associated oncogenes such as LCK and PLCB1, and tumor suppressors such as STAT5A, PTPN6, PARK2. We identified expression levels of genes within significant LOH/AI regions specific to stroma networks that correlate with better outcome in radiation therapy. By integrating various levels of high-throughput data, we were able to precisely focus on specific proteins and genes that are germane to HNSCC.HNSCC is the sixth most common cancer and remains a major cause of cancer morbidity and mortality worldwide [1]. More than 85% of head and neck squamous cell carcinomas (HNSCC) are related to tobacco use, while others may have a relationship to viral etiologies such as human papillomavirus (HPV) infection/colonization. Nevertheless, advanced stage HNSCC remains an aggressive cancer with low survival rates. Molecular studies suggest that HNSCC results from cumulative epigenetic and genetic alterations [2-4]. Various genomic regions and/or genes have been correlated with survival in HNSCC or classified as early detection/aggressiveness markers [2]. Albeit incomplete, such baseline knowledge of HNS
Integrative Genomic Analysis Reveals Extended Germline Homozygosity with Lung Cancer Risk in the PLCO Cohort
Mohammed S. Orloff, Li Zhang, Gurkan Bebek, Charis Eng
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031975
Abstract: Susceptibility to common cancers is multigenic resulting from low-to-high penetrance predisposition-factors and environmental exposure. Genomic studies suggest germline homozygosity as a novel low-penetrance factor contributing to common cancers. We hypothesized that long homozygous regions (tracts-of-homozygosity [TOH]) harbor tobacco-dependent and independent lung-cancer predisposition (or protection) genes. We performed in silico genome-wide SNP-array-based analysis of lung-cancer patients of European-ancestry from the PLCO screening-trial cohort to identify TOH regions amongst 788 cancer-cases and 830 ancestry-matched controls. Association analyses was then performed between presence of lung cancer and common(c)TOHs (operationally defined as 10 or more subjects sharing ≥100 identical homozygous calls), aTOHs (allelically-matched groups within a cTOH), demographics and tobacco-exposure. Finally, integration of significant c/aTOH with transcriptome was performed to functionally-map lung-cancer risk-genes. After controlling for demographics and smoking, we identified 7 cTOHs and 5 aTOHs associated with lung cancer (adjusted p<0.01). Three cTOHs were over-represented in cases over controls (OR = 1.75–2.06, p = 0.007–0.001), whereas 4 were under-represented (OR = 0.28–0.69, p = 0.006–0.001). Interaction between smoking status and cTOH3/aTOH2 (2p16.3–2p16.1) was observed (adjusted p<0.03). The remaining significant aTOHs have ORs 0.23–0.50 (p = 0.004–0.006) and 2.95–3.97 (p = 0.008–0.001). After integrating significant cTOH/aTOHs with publicly-available lung-cancer transcriptome datasets followed by filtering based on lung cancer and its relevant pathways revealed 9 putative predisposing genes (p<0.0001). In conclusion, differentially-distributed cTOH/aTOH genomic variants between cases and controls harbor sets of plausible differentially-expressed genes accounting for the complexity of lung-cancer predisposition.
Group-Based Imputation and the International Criminal Law Discourse. Individuals and Associations as International Criminal Wrongdoers  [PDF]
Charis Papacharalambous
Beijing Law Review (BLR) , 2013, DOI: 10.4236/blr.2013.44016
Abstract:

Collective agency is resurfacing within International Criminal Law (ICL) discourse; its genealogical traces can be found in socio-legal contexts like in systemic theories of liability, victimization-centered approaches and criminal policy models transforming traditional criminal law provisions into “combat norms”. At the intersection between moral theories and law discourse, one can also trace as similar traits the discussions on the relations between corporations’ and purely collective patterns of imputation, whereby selflessness is the main normative characteristic of the wrongdoer. At the level of criminal law, theorizing collective guilt can be made thematic through the methodological turn towards collectivism, the promotion of an aggregate knowledge model as appropriate liability form and the normative orientation towards the criterion of concerted action as individually imputable collective wrong. The qualified forms of co-perpetration within ICL discourse (like the “Joint Criminal Enterprise”, the “Organized Structures of Power” or the “Joint Control of Crime”) are then considered as slippery and ethnocentric hermeneutic tools for translating collective imputation into legal linguistics. Thereby recent developments in the jurisdiction of the International Criminal Court as well as in this of the newer internationalized courts are accordingly analyzed.

Linkage Disequilibrium between Two High-Frequency Deletion Polymorphisms: Implications for Association Studies Involving the glutathione-S transferase (GST) Genes
Yongzhong Zhao,Michael Marotta,Evan E. Eichler,Charis Eng,Hisashi Tanaka
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000472
Abstract: Copy number variations (CNVs) represent a large source of genetic variation in humans and have been increasingly studied for disease association. A deletion polymorphism of the gene encoding the cytosolic detoxification enzyme glutathione S-transferase theta 1 (GSTT1) has been extensively studied for cancer susceptibility (919 studies, from HuGE navigator, http://www.hugenavigator.net/). However, clear conclusions have not been reached. Since the GSTT1 gene is located within a genomic region of segmental duplications (SD), there may be a confounding effect from another, yet-uncharacterized CNV at the same locus. Here we describe a previously uncharacterized 38-kilo-base (kb) long deletion polymorphism of GSTT2B located within a 61-kb DNA inverted repeat. GSTT2B is a duplicated copy of GSTT2, the only paralogue of GSTT1 in humans. A newly developed PCR assay revealed that a microhomology-mediated breakpoint appears to be shared among individuals at high frequency. The GSTT2B deletion polymorphism was in strong linkage disequilibrium (LD) (D′ = 0.841) with the neighboring GSTT1 deletion polymorphism in the Caucasian population. Alleles harboring a single deletion were significantly overrepresented (p = 2.22×10?16), suggesting a selection against alleles with both deletions. The deletion alleles are almost certainly the derived ones, because the GSTT2B-GSTT2-GSTT1 genes were strictly retained in chimpanzees. Extremely low GSTT2 mRNA expression was associated with the GSTT2B deletion, suggesting an influence of the deletion on the flanking region and loss of GSTT2 function. Genome-wide LD analysis between deletion polymorphisms further points to the uniqueness of two deletions, because strong LD between deletion polymorphisms might be very rare in humans. These results show a complex genomic organization and unexpected biological functions of CNVs within segmental duplications and emphasize the importance of detailed structural characterization for disease association studies.
A reinvestigation of somatic hypermethylation at the PTEN CpG island in cancer cell lines
Luke B Hesson, Deborah Packham, Emily Pontzer, Pauline Funchain, Charis Eng, Robyn L Ward
Biological Procedures Online , 2012, DOI: 10.1186/1480-9222-14-5
Abstract: Using a range of bisulphite-based PCR assays we investigated 6 regions across the PTEN CpG island. We found that regions 1-4 were not methylated in cancer cell lines (0/36). By allelic bisulphite sequencing and pyrosequencing methylation was detected in regions 5 and 6 in colorectal, breast and haematological cancer cell lines. However, methylation detected in this region was associated with the PTENP1 promoter and not the PTEN CpG island.We show that methylation of the PTEN CpG island is a rare event in cancer cell lines and that apparent methylation most likely originates from homologous regions of the PTENP1 pseudogene promoter. Future studies should utilize assays that reliably discriminate between PTEN and PTENP1 to avoid data misinterpretation.Phosphatase and tensin homologue (PTEN) is a tumour suppressor gene with dual protein and lipid phosphatase activity. The main mechanism by which PTEN functions as a tumour suppressor is by negatively regulating the PI3K-AKT-mTOR pathway [1,2]. Inactivating germline mutations of PTEN result in a group of rare syndromes collectively known as the PTEN hamartoma tumour syndromes (PHTS), which includes Cowden syndrome and Bannayan-Zonana syndrome [3]. Germline mutations of PTEN account for approximately 80% of Cowden syndrome cases [4]. This syndrome is characterised by a range of clinical features including an increased risk of breast, thyroid and endometrial cancers [3]. Mutation of the PTEN tumour suppressor gene also occurs in various sporadic cancers, including 38% of endometrial, 14% of prostate, 7% of colorectal and 5% of lung carcinomas [5].Promoter CpG island hypermethylation, which can result in the transcriptional silencing of gene expression, is an alternative mechanism of gene inactivation. The importance of PTEN inactivation in PHTS and several types of sporadic cancers makes the gene an attractive candidate for epigenetic inactivation. The PTEN CpG island is shared with another gene, known as KLLN, which is tr
Heritable clustering and pathway discovery in breast cancer integrating epigenetic and phenotypic data
Zailong Wang, Pearlly Yan, Dustin Potter, Charis Eng, Tim Huang, Shili Lin
BMC Bioinformatics , 2007, DOI: 10.1186/1471-2105-8-38
Abstract: Using this heritable clustering approach, we analyzed methylation data obtained from 86 primary breast cancers to recapitulate pathways of breast tumor progression. Detailed annotation and interpretation are provided to the optimal pathway recapitulated. The result confirms the previous observation that aggressive tumors tend to exhibit higher levels of promoter hypermethylation.Our results indicate that the proposed heritable clustering algorithms are a useful tool for stratifying both methylation and clinical variables of breast cancer. The application to the breast tumor data illustrates that this approach can select meaningful progression models which may aid the interpretation of pathways having biological and clinical significance. Furthermore, the framework allows for other types of biological data, such as microarray gene expression or array CGH data, to be integrated.Recapitulating pathways of tumor progression by tracing specific molecular lesions is necessary for understanding the disease and for developing novel drug targets and therapies. The idea of utilizing DNA methylation profiles to recapitulate tumor progression is even more enticing in that these epigenetic marks are stable and heritable in tumor genomes [1]. Specifically, this event occurs by the addition of a methyl group to a cytosine residue of a CpG dinucelotide [2]. It is recognized that in the normal genome, DNA methylation plays a role in mammalian development, imprinting, and X chromosome inactivation [3]. Recent advances further highlight a critical role of epigenetically mediated gene silencing in tumorigenesis [1]. Unmethylated CpG islands, located in the promoter regions of tumor suppressor/gatekeeper genes, become densely methylated during tumorigenesis [4-6]. Once the de novo methylation takes place, this new mark is maintained in subsequent cycles of cell replication by DNA methyltransfereases and other associated proteins, like polycomb repressors [7,8]. The consequence of these
A novel mutation in the tyrosine kinase domain of ERBB2 in hepatocellular carcinoma
Tanios Bekaii-Saab, Nita Williams, Christoph Plass, Miguel Calero, Charis Eng
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-278
Abstract: We extracted genomic DNA from 40 hepatoma (18) and biliary cancers (22) samples, and 44 adenocarcinomas of the lung, this latter as a positive control for mutation detection. We subjected those samples to PCR-based semi-automated double stranded nucleotide sequencing targeting exons 18–21 of EGFR and ERBB2. All samples were tested against matched normal DNA.We found 11% of hepatoma, but no biliary cancers, harbored a novel ERBB2 H878Y mutation in the activating domain.These newly described mutations may play a role in predicting response to EGFR-targeted therapy in hepatoma and their role should be explored in prospective studies.Mutations in the protein-kinase enzyme family, such as the epidermal growth factor receptor (EGFR, ERBB2), found in human cancers are being investigated as promising targets for the development of novel antitumor therapies.EGFR is the first described member of a family of related transmembrane receptor tyrosine kinases. It is comprised of the following four related receptors: EGFR itself (ERBB1 or HER1), ERBB2 (HER2/neu), ERBB3 (HER3) and ERBB4 (HER4). ERBB receptors are composed of an extracellular ligand-binding domain, a transmembrane segment, and an intracellular protein tyrosine kinase domain. These receptors trigger downstream signaling pathways that are complex and multilayered. Deregulation of those ERBB receptors can lead to malignant transformation. These receptors form either homo- or heterodimeric complexes which provides amplification and diversification [1]. Heterodimerization of the ERBB2 and EGFR is associated with a more robust signaling than homodimerization [2]. Several studies showed that gain-of-function somatic mutations affecting the catalytic domain (specifically the ATP binding site, exons 18–21) of EGFR in non-small cell lung carcinomas were strongly associated with response to gefitinib and erlotinib, both related EGFR-tyrosine kinase inhibitors (TKI) [3-5]. More recently, a number of studies reported the presence
Two-dimensional gel proteome reference map of blood monocytes
Ming Jin, Philip T Diaz, Tran Bourgeois, Charis Eng, Clay B Marsh, Haifeng M Wu
Proteome Science , 2006, DOI: 10.1186/1477-5956-4-16
Abstract: In this study, monocytes were isolated from five healthy donors. Whole monocyte lysates from each donor were then analyzed by 2D gel electrophoresis, and proteins were detected using Sypro Ruby fluorescence and then examined for phosphoproteomes using ProQ phospho-protein fluorescence dye. Between 1525 and 1769 protein spots on each 2D gel were matched, analyzed, and quantified. Abundant protein spots were then subjected to analysis by mass spectrometry. This report describes the protein identities of 231 monocyte protein spots, which represent 164 distinct proteins and their respective isoforms or subunits. Some of these proteins had not been previously characterized at the protein level in monocytes. Among the 231 protein spots, 19 proteins revealed distinct modification by protein phosphorylation.The results of this study offer the most detailed monocyte proteomic database to date and provide new perspectives into the study of monocyte biology.Blood monocytes belong to the human mononuclear phagocyte system which plays an important role in a variety of homeostatic processes including host defense, immunoregulation, and tumor surveillance [1-3]. Derived from bone marrow monoblasts, monocytes circulate in the blood for 1–2 days and then enter various tissues to differentiate into macrophages that exhibit specific activities [4-6]. Blood monocytes regulate host inflammatory processes through chemotaxis, pinocytosis/phagocytosis, and the release of cytokines [1,2,7,8]. However, the molecular details underlying these diverse biological activities are not well defined. Recent advances in proteomics have made it possible to gain a global perspective of the protein constituents and their properties in blood monocytes. Analysis of a monocyte proteome and phosphoproteome enables us to learn more about monocyte biology and better understand the mechanisms of diseases involving blood monocytes.One previous study demonstrated the feasibility of monocyte proteome analysis by 2
cgaTOH: Extended Approach for Identifying Tracts of Homozygosity
Li Zhang, Mohammed S. Orloff, Sean Reber, Shengchao Li, Ye Zhao, Charis Eng
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057772
Abstract: Identification of disease variants via homozygosity mapping and investigation of the effects of genome-wide homozygosity regions on traits of biomedical importance have been widely applied recently. Nonetheless, the existing methods and algorithms to identify long tracts of homozygosity (TOH) are not able to provide efficient and rigorous regions for further downstream association investigation. We expanded current methods to identify TOHs by defining “surrogate-TOH”, a region covering a cluster of TOHs with specific characteristics. Our defined surrogate-TOH includes cTOH, viz a common TOH region where at least ten TOHs present; gTOH, whereby a group of highly overlapping TOHs share proximal boundaries; and aTOH, which are allelically-matched TOHs. Searching for gTOH and aTOH was based on a repeated binary spectral clustering algorithm, where a hierarchy of clusters is created and represented by a TOH cluster tree. Based on the proposed method of identifying different species of surrogate-TOH, our cgaTOH software was developed. The software provides an intuitive and interactive visualization tool for better investigation of the high-throughput output with special interactive navigation rings, which will find its applicability in both conventional association studies and more sophisticated downstream analyses. NCBI genome map viewer is incorporated into the system. Moreover, we discuss the choice of implementing appropriate empirical ranges of critical parameters by applying to disease models. This method identifies various patterned clusters of SNPs demonstrating extended homozygosity, thus one can observe different aspects of the multi-faceted characteristics of TOHs.
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