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PubMed2002

Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a debilitating illness lacking consistent anatomic lesions and eluding conventional laboratory diagnosis. Demonstration of the utility of the blood for gene expression profiling and biomarker discovery would have implications into the pathophysiology of CFS. The objective of this study was to determine if gene expression profiles of peripheral blood mononuclear cells (PMBCs) could distinguish between subjects with CFS and healthy controls. Total RNA from PBMCs of five CFS cases and seventeen controls was labeled and hybridized to 1764 genes on filter arrays. Gene intensity values were analyzed by various classification algorithms and nonparametric statistical methods. The classification algorithms grouped the majority of the CFS cases together, and distinguished them from the healthy controls. Eight genes were differentially expressed in both an age-matched case-control analysis and when comparing all CFS cases to all controls. Several of the differentially expressed genes are associated with immunologic functions (e.g., CMRF35 antigen, IL-8, HD protein) and implicate immune dysfunction in the pathophysiology of CFS. These results successfully demonstrate the utility of the blood for gene expression profiling to distinguish subjects with CFS from healthy controls and for identifying genes that could serve as CFS biomarkers.

Adult↗

PubMed2002

Integrin gene expression profiles of human hepatocellular carcinoma.

AIM: To investigate gene expression profiles of integrin genes in hepatocellular carcinoma (HCC) through the usage of Atlas Human Cancer Array membranes, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and Northern blot. METHODS: Hybridization of cDNA array membrane was performed with alpha(32)P-labeled cDNA probes synthesized from RNA isolated from hepatocellular carcinoma and adjacent non-cirrhotic liver. AtlasImage, which is a software specific to array, was used to analyze the result. RT-PCR of 24 pairs specimen and Northern blot of 4 pairs specimen were used to confirm the expression pattern of some integrin genes identified by Atlas arrays hybridization. RESULTS: Among 588 genes spotted in membrane, 17 genes were related to integrin. Four genes were up-regulated, such as integrin alpha8, beta1, beta7 and beta8 in HCC. Whereas there were no genes down-regulated in HCC. RT-PCR and Northern blot analysis of integrin beta1 gene gave results consistent with cDNA array findings. CONCLUSION: Investigation of these integrin genes should help to disclose the molecular mechanism of the cell adhesion, invasive and metastasis of HCC. A few genes are reported to have changed in HCC for the first time. The quick and high-throughout method of profiling gene expression by cDNA array provides us overview of key factors that may involved in HCC, and may find the clue of the study of HCC metastasis and molecular targets of anti-metastasis therapy. The precise relationship between the altered genes and HCC is a matter of further investigation.

Carcinoma, Hepatocellular↗

PubMed2002

Expression profiles of 290 ESTs mapped to chromosome 3 in human epithelial ovarian cancer cell lines using DNA expression oligonucleotide microarrays.

We have investigated previously the utility of oligonucleotide expression microarray technology in an analysis of four spontaneously transformed epithelial ovarian cancer (EOC) cell lines, TOV-21G, TOV-81D, OV-90, and TOV-112D. Here, we examine the expression of 290 expressed sequence tags (ESTs) that map to human chromosome 3 in a primary culture derived from normal ovarian surface epithelium (NOSE), NOV-31, and the four spontaneously transformed EOC cell lines. One of these cell lines, OV-90, harbors a deletion of an entire chromosome 3p arm. Whereas the most aggressive cell lines (OV-90, TOV-112D, and TOV-21G) exhibited the highest levels of expression, assessed by the mean of expression values of all ESTs, OV-90 showed the lowest mean of expression of ESTs that map to the 3p arm in comparison with TOV-112D and TOV-21G. This difference in expression profile of 3p ESTs in OV-90 is also reflected in the ratio of expression of ESTs on 3p versus the 3q arm and in that the expression values of ESTs that map to 3p were more often lower than higher in OV-90 in two-way comparisons with NOV-31, TOV-21G, and TOV-112D. The loss of a 3p arm does not affect the pattern of differential expression in analyses based on the range of numeric expression values of each EST or fold differences in expression for each EST in comparison with NOV-31. However, 25 differentially expressed ESTs were identified on the basis of threefold differences in expression values between NOV-31 and any EOC cell line; and six of these ESTs were differentially expressed uniquely in OV-90. The investigation of these ESTs could facilitate the identification of novel chromosome 3 genes implicated in ovarian tumorigenesis.

Chromosome Mapping↗

PubMed2002

Expression profiling reveals metabolic and structural components of extraocular muscles.

The extraocular muscles (EOM) are anatomically and physiologically distinct from other skeletal muscles. EOM are preferentially affected in mitochondrial myopathies, but spared in Duchenne's muscular dystrophy. The anatomical and pathophysiological properties of EOM have been attributed to their unique molecular makeup: an allotype. We used expression profiling to define molecular features of the EOM allotype. We found 346 differentially expressed genes in rat EOM compared with tibialis anterior, based on a twofold difference cutoff. Genes required for efficient, fatigue-resistant, oxidative metabolism were increased in EOM, whereas genes for glycogen metabolism were decreased. EOM also showed increased expression of genes related to structural components of EOM such as vessels, nerves, mitochondria, and neuromuscular junctions. Additionally, genes related to specialized functional roles of EOM such as the embryonic and EOM-specific myosin heavy chains and genes for muscle growth, development, and/or regeneration were increased. The EOM expression profile was validated using biochemical, structural, and molecular methods. Characterization of the EOM expression profile begins to define gene transcription patterns associated with the unique anatomical, metabolic, and pathophysiological properties of EOM.

Animals↗

PubMed2002

Identifying immunotherapeutic targets for prostate carcinoma through the analysis of gene expression profiles.

Carcinoma of the prostate represents one of the most frequently diagnosed cancers in men. If detected at an early stage, prostate cancer is highly treatable. However, cancers identified at a late stage are rarely cured with contemporary medical therapies. Early detection strategies presently center on the identification of prostate-specific proteins in the serum, and emerging therapeutics have utilized genes and proteins with prostate-restricted expression for tissue-selective immunological regimens incorporating vaccines, dendritic cell therapy, gene therapy, and antibody-based cell targeting. In order to develop improved therapeutic procedures, efforts have been directed toward the identification of genes exhibiting prostate-restricted expression profiles, or altered expression levels in neoplastic cells relative to their normal counterparts. Comprehensive expression profiling approaches such as the analysis of oligonucleotide- or complementary DNA (cDNA)-microarrays have greatly enhanced these efforts. Genes and their cognate proteins identified using such methods offer additional diagnostic and therapeutic targets that may aid in the understanding and treatment of prostate carcinoma.

Acid Phosphatase↗

PubMed2003

Transcriptional gene expression profiling of small cell lung cancer cells.

A global gene expression analysis using oligonucleotide microarrays was performed on many human small cell lung cancer (SCLC) cell lines in cell culture and/or as xenografts. The expression was compared with the expression profiles of 18 normal tissues. In a hierarchical cluster analysis the cell lines clustered distinctly from normal tissues and grouped into four clusters. One cluster consisted of two related cell lines and was markedly different from the other SCLC cell lines, whereas the rest of the clusters grouped together. Two subclusters contained the classical SCLC types and one subcluster the variant SCLC type, thus identifying many genes with differential expression between the two variants of SCLC. All of the xenografts clustered closest to the cell lines from which they originated and had the same expression levels as the cells grown in culture for the majority of genes. The analysis confirmed the high expression of many genes identified previously as highly expressed in SCLC cells including neuroendocrine markers, oncogenes, and genes involved in cell proliferation and division. The analysis furthermore identified a number of molecules not identified previously as expressed in SCLC. Several of these are expressed in low or undetectable amounts in the majority of normal tissues and, therefore, are potential targets for new therapeutic approaches. By including the published array profiles of six ressected SCLC tumors from Bhattacharjee et al. (A. Bhattacharjee et al., Proc. Natl. Acad. Sci. USA, 98: 13790-13795, 2001.), the analysis revealed that most of the novel potential targets expressed by SCLC cell lines and xenografts were also expressed in the tumors. This analysis demonstrates the value of using cell lines and xenografts for expression profiling, when a limited quantity of tumor material is available.

Adult↗

PubMed2003

Expression profiling of breast cancer cells by differential peptide display.

Expression profiling of RNAs or proteins has become a promising means to investigate the heterogeneity of histopathologically defined classes of cancer. Peptides, representing degradation as well as processing products of proteins offer an even closer insight into cell physiology. Peptides are related to the turnover of cellular proteins and are capable to reflect disease-related changes in homoeostasis of the human body. Furthermore, peptides derived from tumor cells are potentially useful markers in the early detection of cancer. In this study, we introduced a method called differential peptide display (DPD) for separating, detecting, and identifying native peptides derived from whole cell extracts. This method is a highly standardized procedure, combining the power of reversed-phase chromatography with mass spectrometry. This technology is suitable to analyze cell lines, various tissue types and human body fluids. Peptide-based profiling of normal human mammary epithelial cells (HMEC) and the breast cancer cell line MCF-7 revealed complex peptide patterns comprising of up to 2300 peptides. Most of these peptides were common to both cell lines whereas about 8% differed in their abundance. Several of the differentially expressed peptides were identified as fragments of known proteins such as intermediate filament proteins, thymosins or Cathepsin D. Comparing cell lines with native tumors, overlapping peptide patterns were found between HMEC and a phylloides tumor (CP) on the one hand and MCF-7 cells and tissue from a invasive ductal carcinoma (DC) on the other hand.

Biomarkers, Tumor↗

PubMed2003

Novel potential ALL low-risk markers revealed by gene expression profiling with new high-throughput SSH-CCS-PCR.

The current systems of risk grouping in pediatric acute lymphoblastic leukemia (ALL) fail to predict therapeutic success in 10-35% of patients. To identify better predictive markers of clinical behavior in ALL, we have developed an integrated approach for gene expression profiling that couples suppression subtractive hybridization, concatenated cDNA sequencing, and reverse transcriptase real-time quantitative PCR. Using this approach, a total of 600 differentially expressed genes were identified between t(4;11) ALL and pre-B ALL with no determinant chromosomal translocation. The expression of 67 genes was analyzed in different cytogenetic ALL subgroups and B lymphocytes isolated from healthy donors. Three genes, BACH1, TP53BPL, and H2B/S, were consistently expressed as a significant cluster associated with the low-risk ALL subgroups. A total of 42 genes were differentially expressed in ALL vs normal B lymphocytes, with no specific association with any particular ALL subgroups. The remaining 22 genes were part of a specific expression profile associated with the hyperdiploid, t(12;21), or t(4;11) subgroups. Using an unsupervised hierarchical cluster analysis, the discriminating power of these specific expression profiles allowed the clustering of patients according to their subgroups. These genes could help to understand the difference in treatment response and become therapeutical targets to improve ALL clinical outcomes.

B-Lymphocytes↗

PubMed2000

Uncovering functionally relevant signaling pathways using microarray-based expression profiling.

The introduction of microarray technology to the scientific and medical communities has fundamentally altered the way in which we now address basic biomedical questions. Microarrays technology facilitates a more complete and inclusive experimental approach where alterations in the transcript level of entire genomes can be simultaneously assayed in response to a variety of stimuli. Conceptually different approaches to the development of microarray technology have resulted in the generation of two different array formats: oligonucleotide arrays and cDNA arrays. The application of microarray and related technologies to identify specific targets of defined genes that have clearly been implicated in cancer progression requires a specific experimental approach. The objective of this approach is to define changes in transcriptional profile that occur in response to modulating the expression level of the gene to be studied. The resulting altered expression profile can then be viewed as a blueprint by which that gene effects its cellular function. We have used oligonucleotide array-based expression profiling in collaboration with Affymetrix to identify downstream transcriptional targets of the BRCA1 tumor-suppressor gene as a means of defining its function. BRCA1 has been implicated in at least three functional pathways, namely, mediating the cellular response to DNA damage, as a cell cycle checkpoint protein and in the regulation of transcription. The physiological significance of these properties and their implications for the function of BRCA1 as a tumor-suppressor gene remain to be defined.

DNA, Complementary↗

PubMed2000

Novel strategies for therapeutic design in molecular oncology using gene expression profiles.

The sequence of the human genome is estimated to be available by the end of the year 2000 [1]. Pursuant to deciphering the genomic code, and the identification of the estimated 40,000 to 100,000 human genes, anticipated technological advances will make possible examination of global gene expression profiles. Despite the current inaccessibility to the entire genome, many fruitful gene expression profiling studies have been performed using less than 10% of the predicted suite of genes in human or mouse genomes. Even within the confines of this limited set of genes, many insights and discoveries have resulted and their applications to cancer research are particularly profound. This review will focus on recent applications of gene expression profiling that have benefited three major areas of research in molecular oncology: (i) discovery--applications which have found novel genes, families of genes, or pathways involved in cell growth deregulation and tumor development; (ii) diagnosis--applications that have refined, and in some cases, defined, diagnostic methodology; and (iii) therapeutic design--applications which hold potential for chemotherapeutic drug discovery.

Animals↗

PubMed2002

Distinction in gene expression profiles of oligodendrogliomas with and without allelic loss of 1p.

Oligodendrogliomas frequently, but not always show sensitivity to chemotherapy and recent studies demonstrated that allelic loss of chromosome 1p is highly associated with this chemosensitivity. To gain insight into the molecular mechanism of such difference, we examined comprehensive gene expression profiles of 11 oligodendroglial tumors, six with and five without 1pLOH (loss of heterozygosity), and two normal brain tissues using the oligonucleotide microarray (GeneChip). Statistically significant numbers of genes were expressed differentially between the two genetic subsets. Clustering analysis separated the tumor subsets well. The tumors with 1pLOH had similar expression profiles to the normal brain for those differentially expressed genes. Many genes showing higher expression in tumors with 1pLOH were presumed to have functions in nervous tissues. Notably, the majority of the 123 genes showing significant expression reduction in tumors with 1pLOH were either on chromosome 1 (50%) or on 19 (10%), and the average expression reduction ratio was about 50% (0.54+/-0.13) possibly reflecting the chromosomal deletion. Thus, the biological difference between the genetic subsets of oligodendroglioma was indeed reflected to gene expression profile, which provided baseline information for further studies to elucidate the mechanism of chemosensitivity in gliomas.

Adult↗

PubMed2001

Gene-expression profiles in hereditary breast cancer.

BACKGROUND: Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The histopathological changes in these cancers are often characteristic of the mutant gene. We hypothesized that the genes expressed by these two types of tumors are also distinctive, perhaps allowing us to identify cases of hereditary breast cancer on the basis of gene-expression profiles. METHODS: RNA from samples of primary tumor from seven carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation, and seven patients with sporadic cases of breast cancer was compared with a microarray of 6512 complementary DNA clones of 5361 genes. Statistical analyses were used to identify a set of genes that could distinguish the BRCA1 genotype from the BRCA2 genotype. RESULTS: Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each other. An analysis of variance between the levels of gene expression and the genotype of the samples identified 176 genes that were differentially expressed in tumors with BRCA1 mutations and tumors with BRCA2 mutations. Given the known properties of some of the genes in this panel, our findings indicate that there are functional differences between breast tumors with BRCA1 mutations and those with BRCA2 mutations. CONCLUSIONS: Significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. Our results suggest that a heritable mutation influences the gene-expression profile of the cancer.

Algorithms↗

PubMed2003

Gene expression profile of aging in human muscle.

Studies of gene expression related to aging of skeletal muscle have included few subjects or a limited number of genes. We conducted the present study to produce more comprehensive gene expression profiles. RNA was extracted from vastus lateralis biopsies obtained from healthy young (21-27 yr old, n = 8) and older men (67-75 yr old, n = 8) and was analyzed with high-density oligonucleotide arrays. Of the approximately 44,000 probe sets on the arrays, approximately 18,000 yielded adequate signals for statistical analysis. There were approximately 700 probe sets for which t-tests or rank sum tests indicated a difference (P <or= 0.01) in mean expression between young and old and for which the estimated false discovery rate was <10%. Most of these differences were less than 1.5-fold in magnitude. Genes that encode proteins involved in energy metabolism and mitochondrial protein synthesis were expressed at a lower level in older muscle. Genes encoding metallothioneins, high-mobility-group proteins, heterogeneous nuclear ribonucleoproteins and other RNA binding/processing proteins, and components of the ubiquitin-proteasome proteolytic pathway were expressed at higher levels in older muscle. Expression of numerous genes involved with stress responses, hormone/cytokine/growth factor signaling, control of the cell cycle and apoptosis, and transcriptional regulation appeared to be affected by aging. More transcripts were detected in older muscle, suggesting dedifferentiation, an increased number of splice variants, or increased cellular heterogeneity. We conclude that in human skeletal muscle the expression of many genes tends to increase or decrease between the third and seventh decades. The changes are modest when averaged over all of the cells in the tissue.

Adult↗

PubMed1999

Representative cDNA libraries and their utility in gene expression profiling.

An increasing interest in gene expression profiles in human diseases has led to the use of microdissected tumors and biopsies in gene discovery approaches. Since many of these clinical samples yield extremely small amounts of RNA, reproducible methods are needed to amplify this RNA while maintaining the original message profile. Using the SMART cDNA Synthesis Method, we show that high-, medium- and low-abundance transcripts can be amplified in a representative fashion and that the resulting cDNA can also be used as a complex probe to confirm gene expression differences identified by other techniques.

DNA, Complementary↗

PubMed2001

Gene expression profiles of pancreatic cancer and stromal desmoplasia.

Gene expression studies were undertaken in normal pancreas and pancreatic adenocarcinomas to determine new candidate genes that can potentially be used as markers of the disease. The characteristic desmoplastic stromal reaction of pancreatic adenocarcinoma greatly hampers expression studies in this tumour type, and usually necessitates time-consuming tissue microdissection for enrichment of the tumour cell population. We show that fine needle aspiration of cancer provides a fast and efficient way of obtaining samples highly enriched in tumour cells with sufficient yields of RNA. Using Atlas cancer cDNA arrays with 588 cancer-related genes, we describe gene expression profiles of normal pancreas, bulk pancreatic tumour tissues and pancreatic tumour aspirates containing more than 95% tumour cells. Analysis of bulk tissue specimens revealed differentially expressed genes belonging predominantly to the stromal component of the tumour. This contrasted with the results obtained from tumour-cell enriched samples. Several genes already described in pancreatic cancer (caspase 8, TIMP1, CD9, IL-13) were also differentially expressed in our study. Furthermore, we found dysregulated expression of genes not previously associated with pancreatic adenocarcinoma, such as Rac 1, GLG1, NEDD5, RPL-13a, RPS9 and members of the Wnt5A gene family. In summary, we present a panel of genes newly identified in the pathogenesis of pancreatic adenocarcinoma and demonstrate that fine needle aspirates of the tumour mass are a convenient source of material for gene expression studies in tumours accompanied by desmoplastic reactions.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Insight into lymphoid development by gene expression profiling of avian B cells.

The avian immune system provides an excellent model to track B-cell development from prebursal stem cells throughout B-cell differentiation and maturation. Bursal B cells are uniquely positioned at the crossroads of B-cell development, having properties of both stem cells and of mature B cells, as demonstrated by their ability to reconstruct the bursal B-cell compartment and to express and diversify the B-cell receptor at their cell surface. To understand avian B-cell development better, we determined the gene expression profile of different B-cell stages using a bursal expressed sequence tag array. The expression profile of bursal B cells reveals the presence of factors associated with B-cell signaling and defines novel B-cell-specific genes. Genes associated with proliferation, apoptosis, DNA repair and recombination are abundantly expressed. The expression profile of the DT40 cell line is most similar to bursal B cells rather than to other stages of B-cell development, confirming the suitability of DT40 for studies of B-cell physiology. Interestingly, prebursal stem cells express genes involved in B-cell receptor signaling, although they express only low levels of immunoglobulin genes. This suggests that B-cell receptor-mediated selection is present before bursal colonization. The gene expression signatures of germinal centers and cells of the Harderian gland indicate that evolutionarily conserved genetic programs regulate B-cell activation and terminal differentiation.

Animals↗

PubMed2002

Identifying cancer-related genes in nasopharyngeal carcinoma cell lines using DNA and mRNA expression profiling analyses.

The goals of this study were to evaluate the potential of detecting cryptic amplification and deletion of cancer-related genes using array-based comparative genomic hybridization (CGH), and to identify candidate cancer genes by combined parallel analyses of copy number and gene expression profiles in nasopharyngeal carcinoma (NPC) cell lines. We established global DNA copy number and mRNA expression profiles on human NPC cell lines using a high-density cDNA microarray. The DNA copy number alterations detected by array CGH were compared to the DNA copy number variations identified by metaphase CGH. A cryptic amplification at 3q26 was detected by array CGH, which was not found by metaphase CGH. By amplicon mapping and parallel analyses of DNA copy number and mRNA expression levels, we identified several candidates which could be important mediators in tumor formation or progression. Taken together, the combination of copy number and gene expression profiling using cDNA microarrays provides an improved strategy for gene discovery in human cancer.

Biomarkers, Tumor↗

PubMed2003

Gene expression profiling of melanocytic lesions.

DNA microarrays, microscopic grids of DNA, can be used to assess gene expression within a particular cell or cell population. Since DNA from thousands of genes can be hybridized and analyzed in one experiment, researchers can globally characterize genes expressed in normal and various pathologic states. To accurately assess the differences between normal and pathologic states, one derives cDNA from control and diseased tissue specimens for genes expression profiling. For these reasons, microarray technology may be of particular interest to dermatopathologists and dermatologists interested in understanding cutaneous disease because these physicians have access to tissue specimens. In addition, microarray technology is an efficient way of identifying molecules expressed in a cell population; therefore, it can be used to search for unique immunohistologic markers. To this end, we have used microarray technology to define differences in the gene expression profile of nevi and melanomas. In this manuscript, we discuss the results of our study, which confirm previously known differences in gene expression between melanoma and nevi. While a few genes appear slightly overexpressed in nevi, a number of genes involved in regulating cell proliferation were upregulated in melanoma, such as cyclin D1, cdc2-related protein kinase, c-Myc binding protein, early growth response protein 1, and pleiotrophin. "Housekeeping" genes such as glyceraldehyde 3-phosphate dehydrogenase were expressed at similar levels in melanoma and nevi. Surprisingly, a majority of genes were expressed at similar levels in both nevi and melanoma. Based on this study, DNA microarray technology appears to be a valuable tool for identifying genes that may be specifically expressed in cutaneous lesions.

Biomarkers, Tumor↗