Prognostic classification of breast cancer and gene expression profiling

Clinical and pathological heterogeneity of breast cancer, partly responsible of therapeutic failures, reflects complex and combinatory molecular alterations until now poorly documented by classical investigation tools. Thorough molecular typing is crucial. The advent of DNA microarray-based gene expression profiling allowed consistent progresses in this direction. A novel molecular taxonomy of breast cancer has been defined, signatures that predict clinical outcome or therapeutic response have been identified, some of them being tested in ongoing prospective clinical trials. In this review, we present the main results and their potential clinical applications. We also discuss their current limits and future hopes in the therapeutic management of patients.     

The ankyrin repeat gene family in rice: genome-wide identification,classification and expression profiling

Ankyrin repeat (ANK) containing proteins comprise a large protein family. Although many members of this family have been implicated in plant growth, development and signal transduction, only a few ANK genes have been reported in rice. In this study, we analyzed the structures, phylogenetic relationship, genome localizations and expression profiles of 175 ankyrin repeat genes identified in rice (OsANK). Domain composition analysis suggested OsANK proteins can be classified into ten subfamilies. Chromosomal localizations of OsANK genes indicated nine segmental duplication events involving 17 genes and 65 OsANK genes were involved in tandem duplications. The expression profiles of 158 OsANK genes were analyzed in 24 tissues covering the whole life cycle of two rice genotypes, Minghui 63 and Zhenshan 97. Sixteen genes showed preferential expression in given tissues compared to all the other tissues in Minghui 63 and Zhenshan 97. Nine genes were preferentially expressed in stamen of 1 day before flowering, suggesting that these genes may play important roles in pollination and fertilization. Expression data of OsANK genes were also obtained with tissues of seedlings subjected to three phytohormone (NAA, GA3 and KT) and light/dark treatments. Eighteen genes showed differential expression with at least one phytohormone treatment while under light/dark treatments, 13 OsANK genes showed differential expression. Our data provided a very useful reference for cloning and functional analysis of members of this gene family in rice. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Perspectives and limitations of gene expression profiling in rheumatology: new molecular strategies

The deciphering of the sequence of the human genome has raised the expectation of unravelling the specific role of each gene in physiology and pathology. High-throughput technologies for gene expression profiling provide the first practical basis for applying this information. In rheumatology, with its many diseases of unknown pathogenesis and puzzling inflammatory aspects, these advances appear to promise a significant advance towards the identification of leading mechanisms of pathology. Expression patterns reflect the complexity of the molecular processes and are expected to provide the molecular basis for specific diagnosis, therapeutic stratification, long-term monitoring and prognostic evaluation. Identification of the molecular networks will help in the discovery of appropriate drug targets, and permit focusing on the most effective and least toxic compounds. Current limitations in screening technologies, experimental strategies and bioinformatic interpretation will shortly be overcome by the rapid development in this field. However, gene expression profiling, by its nature, will not provide biochemical information on functional activities of proteins and might only in part reflect underlying genetic dysfunction. Genomic and proteomic technologies will therefore be complementary in their scientific and clinical application.     

Molecular classification of scrapie strains in mice using gene expression profiling

Transmissible spongiform encephalopathy strains demonstrate specific prion characteristics, each with specific incubation times, and strain-specific patterns of deposition of the misfolded isoform of prion, PrPSc, in the brains of infected individuals. Different biochemical properties, including glycosylation profiles and the degree of proteinase resistance, have been shown to be strain-specific. However, no relationship between these properties and the phenotypic differences in the subsequent diseases has as yet been determined. Here we explore the utility of gene expression profiles to identify differences in the host response to different strains of prion agent. We identify 114 genes that exhibit significantly different levels of expression in mice infected with three strains of scrapie. These genes represent a pool of genes involved in a strain-specific response to prion disease. We have identified the most discriminatory genes from this list utilizing a wrapper-based feature selection algorithm with external cross-validation.     

The origins of molecular genetics: one gene, one enzyme

Roots presents articles on landmark discoveries that laid the basis for contemporary molecular and cellular biology. In this article, N. H. Horowitz, Professor Emeritus at the California Institute of Technology, and a former associate of George Beadle's, reviews the work that led to the one gene–one enzyme hypothesis.     

Leukotriene receptors: classification,gene expression,and signal transduction

Leukotrienes (LTs) are potent pro-inflammatory mediators derived from arachidonic acid by the action of 5-lipoxygenase. There are two groups of LTs: LTB(4) and cysteinyl LTs (LTC(4), LTD(4), and LTE(4)). Both of them play important roles in many inflammatory diseases and allergic responses. Recently, their G-protein coupled receptors have been cloned. The identification of these receptors enables us to analyze their gene structures, regulation of expression, and signal transduction in the cells, and it also leads to the development of useful antagonists. Some LT receptors have been disrupted by gene targeting. Such studies may reveal novel functions of leukotrienes, confirming deeper viewpoints for further research.     

The genetics of gene expression and gene mapping

A recent publication has shown that a significant portion of gene expression levels are under genetic control in different organisms, that there are hotspot regions in the genome that control the expression of many other genes, and how gene expression data can be used to localize genes that affect clinical traits.     

Microarray-based, high-throughput gene expression profiling of microRNAs

MicroRNAs (miRNAs) are small regulatory RNAs that serve fundamental biological roles across eukaryotic species. We describe a new method for high-throughput miRNA detection. The technique is termed the RNA-primed, array-based Klenow enzyme (RAKE) assay, because it involves on-slide application of the Klenow fragment of DNA polymerase I to extend unmodified miRNAs hybridized to immobilized DNA probes. We used RAKE to study human cell lines and brain tumors. We show that the RAKE assay is sensitive and specific for miRNAs and is ideally suited for rapid expression profiling of all known miRNAs. RAKE offers unique advantages for specificity over northern blots or other microarray-based expression profiling platforms. Furthermore, we demonstrate that miRNAs can be isolated and profiled from formalin-fixed paraffin-embedded tissue, which opens up new opportunities for analyses of small RNAs from archival human tissue. The RAKE assay is theoretically versatile and may be used for other applications, such as viral gene profiling.     

Differential protein expression in human gliomas and molecular insights

Gliomas are the most common of the primary intracranial tumors with astrocytomas constituting about 40%. Using clinically and histologically assessed astrocytomas, we have studied their protein profiles using a two-dimensional gel electrophoresis-mass spectrometry approach and identified differentially expressed proteins which may be useful molecular indicators to understand these tumors. Examination of the protein profiles of 27 astrocytoma samples of different grades revealed 72 distinct, differentially expressed proteins belonging to various functional groups such as cytoskeleton and intermediate filament proteins, heat shock proteins (HSPs), enzymes and regulatory proteins. Based on the consistency of their differential expression, 29 distinct proteins could be short-listed and may have a role in the pathology of astrocytomas. Some were found to be differentially expressed in both Grade III and IV astrocytomas while others were associated with a particular grade. A notable observation was underexpression of Prohibitin, a potential tumor suppressor protein, Rho-GDP dissociation inhibitor, Rho-GDI, a regulator of Rho GTPases and HSPs as well as destabilization of glial fibrillary acidic protein, GFAP, major protein of the glial filaments, in Grade III malignant tumors. We attempt to explain glioma malignancy and progression in terms of their combined role.     

VizStruct: exploratory visualization for gene expression profiling

MOTIVATION: DNA arrays provide a broad snapshot of the state of the cell by measuring the expression levels of thousands of genes simultaneously. Visualization techniques can enable the exploration and detection of patterns and relationships in a complex data set by presenting the data in a graphical format in which the key characteristics become more apparent. The dimensionality and size of array data sets however present significant challenges to visualization. The purpose of this study is to present an interactive approach for visualizing variations in gene expression profiles and to assess its usefulness for classifying samples. RESULTS: The first Fourier harmonic projection was used to map multi-dimensional gene expression data to two dimensions in an implementation called VizStruct. The visualization method was tested using the differentially expressed genes identified in eight separate gene expression data sets. The samples were classified using the oblique decision tree (OC1) algorithm to provide a procedure for visualization-driven classification. The classifiers were evaluated by the holdout and the cross-validation techniques. The proposed method was found to achieve high accuracy. AVAILABILITY: Detailed mathematical derivation of all mapping properties as well as figures in color can be found as supplementary on the web page http://www.cse.buffalo.edu/DBGROUP/bioinformatics/supplementary/vizstruct. All programs were written in Java and Matlab and software code is available by request from the first author.