The promise of molecular profiling for cancer identification and treatment.
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Gene Expression Profiling↗
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Results for “molecular profiling”
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Expression analysis of genes identified by molecular profiling of VGP melanomas and MGP melanoma-positive lymph nodes.
Microarray profiling is a powerful approach to establish gene expression patterns for different histopathological stages of a malignancy, and at the same time, to identify individual genes that may have important functions in the early and/or advanced stages of a neoplasm. To identify genes that hitherto have not been shown to be expressed or play a role in advanced-stage melanomas, we conducted microarray analyses with RNAs from primary melanoma and melanoma-positive lymph node specimens. Using RT-PCR, quantitative, real-time RT-PCR, and fluorochrome oligonucleotide-based optical imaging, we established the level and pattern of expression of five of the identified known genes [Suppression of Tumorigenicity 13 (ST13), Cystatin 8 (CST-8), Dyskeratosis Congentia 1 (DKC1), Neuroendocrine Secretory Protein 55 (NESP55), Niemann-Pick Disease, type C2 (NP-C2)], and a gene with unknown function (16.7 kD Hypothetical Protein) in benign and atypical nevocytic lesions, advanced-stage melanomas, and melanoma-positive lymph nodes.
Base Sequence↗
Molecular profiling of embryonal carcinoma cells following retinoic acid or histone deacetylase inhibitor treatment.
Regulation of tissue homeostasis is crucial to disease prevention; cell division, cell cycle arrest, differentiation and apoptosis have to be tightly controlled in order to maintain this homeostasis. Retinoic acid (RA) and the histone deacetylase inhibitors (HDACIs) have profound effects on these processes and thus may be critical regulators of homeostasis. Consequently, RA and/or histone deacetylase inhibitors are currently being tested in clinical trials for a variety of cancers. Unfortunately, little is known of the overall affect of these compounds on cellular gene expression. Therefore, we decided to compare the effects of all-trans retinoic acid (ATRA) and a particular HDACI-Trichostatin A (TSA)-on an embryonal carcinoma (EC) cell line (F9) using gene chip analysis. We have focused particular attention on those genes that may be differentially affected by these compounds. Within the parameters established for this study, only 116 of the 12,488 genes examined were similarly regulated by ATRA and TSA: 75 positively and 41 negatively. An additional 70 genes were affected by only one of the compounds and 19 genes were actually inversely regulated. The gene set inversely regulated by ATRA and TSA includes several important patterning genes as well as the crucial tumor suppressor/promoter, transforming growth factor beta 1 (TGFbeta1). Promoter analysis suggests a motif that may regulate one set of these genes. This study provides the first comprehensive comparison of global gene expression on EC cells as affected by ATRA and a HDAC inhibitor (TSA); reveals new targets for ATRA and HDAC inhibitors; identifies a new regulatory motif; demonstrates that ATRA and HDAC inhibitors do not always act synergistically on gene expression; and examines particular questions regarding their concurrent clinical application.
Antineoplastic Agents↗
Molecular profiling of transformed and metastatic murine squamous carcinoma cells by differential display and cDNA microarray reveals altered expression of multiple genes related to growth, apoptosis, angiogenesis, and the NF-kappaB signal pathway.
To identify changes in gene expression with transformation and metastasis, we investigated differential gene expression in a squamous carcinoma model established in syngeneic mice. We used mRNA differential display (DD) to detect global differences and cDNA arrays enriched for cancer-associated genes using mRNA from primary keratinocytes, transformed Pam 212 squamous carcinoma cells, and metastases of Pam 212. After DD, 72 candidate cDNAs expressed primarily in transformed and metastatic cells were selected and cloned. Fifty-seven were detected, and 32 were confirmed to be differentially expressed by Northern blot analysis. mRNA expression profiles were also generated using a mouse cDNA array composed of 4000 elements representing known genes and expressed sequence tags plus the 57 DD candidate cDNAs detected by Northern analysis to facilitate data validation. cDNA array detected 76.9% of the differentially expressed mRNAs selected from DD and confirmed by Northern blot, whereas low-abundance mRNAs did not reach the threshold for detection by the lower-sensitivity array method. Clustering analysis of DD and array results from transformed and metastatic cells identified genes that exhibited decreased or increased expression with transformation and metastasis. Alterations in the expression of several genes detected during tumor progression were consistent with their functional activities involving growth (p21, p27, and cyclin D1), resistance and apoptosis (glutathione-S-transferase, cIAP-1, PEA-15, and Fas ligand), inflammation and angiogenesis [chemokine growth-regulated oncogene 1 (also called KC)], and signal transduction (c-Met, yes-associated protein, and syk). Strikingly, 10 of 22 genes in the cluster expressed in metastases have been associated with activation of the nuclear factor (NF)-kappaB signal pathway. The NF-kappaB-inducible cytokine Gro-1 was recently shown to promote tumor growth, metastasis, and angiogenesis of squamous cell carcinomas in vivo (Loukinova et al., Oncogene, 19: 3477-3486, 2000). The results demonstrate that early response genes related to NF-kappaB contribute to metastatic tumor progression. Comparison of cell lines and tumor tissue revealed a concordance of approximately 50% by array, and 70% for Northern-confirmed, metastasis-related genes. Functional genomic approaches comparing expression among cell lines and tumor tissue may promote a better understanding of the genes expressed by malignant and host cells during tumor progression and metastasis.
Animals↗
Molecular profiling of high-risk neuroblastoma by cDNA array.
The aim of this study was to investigate gene expression changes in disseminated neuroblastoma by cDNA array technique. Three stage IV neuroblastomas and one neuroblastoma cell line (SK-N-FI) were analyzed. Expression profiles were confirmed by semiquantitative RT-PCR and in some instances by Northern blotting. Comparison of expression profiles identified several genes which were highly expressed as well as some which were down-regulated in tumor samples relatively to SK-N-FI cells. The tumors studied lacked N-myc overexpression, while showing up-regulation of basic transcription factors, growth factors and receptors such as NSEP, c-myc binding protein MM1, thymosin beta10 (TMSB10), TNF-R superfamily member 10A (TNFRSF10A) and FZ9. These results suggest that cDNA array technology is a powerful tool to identify a set of genes involved in neuroblastoma genesis and progression. Thus, the sensitive cDNA array may provide new insight into many aspects of pediatric tumors and play crucial role in the administration of adjuvant therapy of patients with neuroblastoma.
Child, Preschool↗
Prospective molecular profiling of melanoma metastases suggests classifiers of immune responsiveness.
We amplified RNAs from 63 fine needle aspiration (FNA) samples from 37 s.c. melanoma metastases from 25 patients undergoing immunotherapy for hybridization to a 6108-gene human cDNA chip. By prospectively following the history of the lesions, we could correlate transcript patterns with clinical outcome. Cluster analysis revealed a tight relationship among autologous synchronously sampled tumors compared with unrelated lesions (average Pearson's r = 0.83 and 0.7, respectively, P < 0.0003). As reported previously, two subgroups of metastatic melanoma lesions were identified that, however, had no predictive correlation with clinical outcome. Ranking of gene expression data from pretreatment samples identified approximately 30 genes predictive of clinical response (P < 0.001). Analysis of their annotations denoted that approximately half of them were related to T-cell regulation, suggesting that immune responsiveness might be predetermined by a tumor microenvironment conducive to immune recognition.
Adult↗
Molecular profiling of lymphoma.
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Gene Expression↗
Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes.
This study was designed to characterize the expression profiles of nine bladder cancer cell lines (T24, J82, 5637, HT1376, RT4, SCaBER, TCCSUP, UMUC-3, and HT1197) using cDNA microarrays (8976 genes and expressed sequence tags). Novel targets involved in bladder cancer progression of potential clinical relevance were validated by immunohistochemistry using tissue microarrays of primary bladder tumors (n = 193 cases). Hierarchical clustering classified uroepithelial cells based on their histopathogenesis and cell cycle alterations. Keratin 10 and caveolin-1 transcripts were more abundant in tumor cells from squamous and invasive origin. Their combined expression was shown to stratify bladder tumors and define squamous differentiation. To assess the robustness of the clustering analysis, a bootstrap resampling technique was used. This grouped tumor cell lines based on their biological properties, including cell cycle and cell adhesion features. E-cadherin, zyxin, and moesin were identified as genes differentially expressed in these clusters and related to the p53, RB, and INK4A status of the cell lines. Loss of these adhesion molecules was associated with stage and grade in primary tumors (P < 0.05), and moesin expression was also associated with survival (P = 0.01). Deregulation of cell cycle and apoptotic pathways, such as mutations or altered expression of p53, pRB, and INK4A (p16), is necessary for uroepithelial transformation. However, it appears that deregulation of cell adhesion is a common event associated with tumor progression in uroepithelial neoplasms.
Biomarkers, Tumor↗
Hepatitis B and C in the hemodialysis unit of Tocantins, Brazil: serological and molecular profiles.
A survey was conducted in the hemodialysis population of the state of Tocantins, Brazil, aiming to assess the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, to analyze associated risk factors, and also to investigate these viruses genotypes distribution. During January and March 2001, all patients (n = 100) were interviewed at the unique dialysis unit in Tocantins. Blood samples were collected and serum samples were screened for HBV serological markers. Hepatitis B surface antigen positive samples were tested for HBV DNA. All samples were also tested for anti-HCV antibodies and HCV RNA. An overall prevalence of 45% was found for HBV infection (4% were HBsAg/anti-HBc positive, 2% were anti-HBc only and 39% had anti-HBc/anti-HBs markers). Concerning HCV infection, anti-HCV and HCV RNA were detected in 13% and 14% of the subjects, respectively. Three patients were HCV RNA positive and anti-HCV negative, resulting in an overall HCV prevalence of 16%. Univariate analysis of risk factors showed that only shift and length of tile on hemodialysis were associated with HBV and HCV positivity respectively. Among the four HBsAg-positive samples, HBV DNA was detected in three of them, which were identified as genotype A by restriction fragment length polymorphism (RFLP) analysis. All 14HCV RNA-positive samples were genotyped by INNO-LiPA. Genotypes la and 3a were found in 85% and 15%, respectively. The present data show low HBsAg and HCV prevalence rates. The risk factors associated with HBV and HCV positivity suggest that nosocomial transmission may influence in spreading these viruses in the dialysis unit studied.
Adolescent↗
Molecular profiling: gene expression reveals discrete phases of lens induction and development in Xenopus laevis.
PURPOSE: Experimental tissue transplant studies reveal that lens development is directed by a series of early and late inductive interactions. These interactions impart a growing lens-forming bias within competent presumptive lens ectoderm that leads to specification and the commitment to lens fate. Relatively few genes are known which control these events. Identification of additional genes expressed during lens development may reveal key players in these processes and help to characterize these tissue properties. METHODS: A large suite of genes has been isolated that are expressed during the process of cornea-lens transdifferentiation (lens regeneration) in Xenopus laevis. Many of these genes are also expressed during embryonic lens development. Genes were selected for expression analysis via in situ hybridization. This group consisted of clones with possible roles in cell determination and differentiation as well as novel clones without previous identities. The spatiotemporal expression of these genes in conjunction with previously described genes were correlated with key events during embryonic lens formation. RESULTS: Eighteen of the thirty clones analyzed via in situ hybridization demonstrated observable expression in the developing lens. These genes were initially expressed in the presumptive lens ectoderm at a variety of timepoints throughout development. Expression is restricted to discrete time intervals during lens development. However, in most cases, expression was maintained throughout lens development after being initially upregulated. CONCLUSIONS: The expression of these genes suggests that a genetic hierarchy exists in which an increasing number of genes are upregulated and their expression is maintained throughout lens development. Suites of genes appear to be upregulated at specific timepoints during development, correlating with stages of lens induction, specification, commitment, lens placode formation, and lens differentiation, while suites at additional timepoints suggest that other, previously unreported stages exist as well. This analysis provides a genetic framework for characterizing these processes of lens development.
Animals↗
The role of expression of the components of proteome in the formation of molecular profile of human ovarian carcinoma A2780 cells sensitive and resistant to cisplatin.
AIM: To study the expression of proteins that characterize drug resistance, proliferation and apoptosis of human ovarian carcinoma cells. METHODS: The study was carried out on human ovarian carcinoma A2780 cells and on the A2780/DDP8 subline resistant to cisplatin. Expression of the surface and intracellular antigens (p53, Bcl-2, CD95, antigen of proliferating cells, metallothioneins, drug resistance proteins (P-glycoprotein (P-gp), glutathione-S-transferase), molecules of adhesion (E-cadherin, alpha- and beta-catenins) was studied by immunocytochemical method. RESULTS: It has been shown that the formation of the resistance to cisplatin in A2780/DDP8 cells is accompanied by the increase of expression of glutathione-S-transferase and Bcl-2, by the decrease of expression of CD95-antigene and proliferation potential of the cells, by appearance of EGF receptors and elevation of expression level of E-cadherin, alpha- and beta-catenins, proving the enhancement of adhesive properties of tumor cells. CONCLUSION: Antiapoptotic program seems to be the leading mechanism of the development of the resistance to cisplatin in A2780/DDP8 cells and is realized via high expression of Bcl-2. During the development of drug resistance of A2780/DDP cells, the program of glutathione detoxification is functionally replacing the decrease of the content of metallothioneins.
Antineoplastic Agents↗
Molecular weight profiling of low molecular weight heparins utilizing a heparinase degraded oligosaccharide mixture as a calibrator.
Heparinase degraded heparin fragments (HDHF) are enriched with a UV chromophore and can be utilized as calibrators to determine the molecular weight profile of low molecular weight heparins (LMWH's). In a standard protocol (1), the second to the last peak is assumed to be a hexasaccharide with a molecular weight of 1.8 kDa. All other peak molecular weights in the elution profile are assigned based upon this assumption. In this study, synthetic analogues of heparin with a defined molecular weight have been used to investigate the validity of this assumption. These compounds included a sulfated bis-lactobionic acid amide (2.4 kDa), a pentasaccharide (1.7 kDa), and lactose polysulfate (1.2 kDa). With reference to these internal standards, the second to the last peak of the HDHF mixture was found to elute after the pentasaccharide and close to the lactose polysulfate suggesting that it is a tetrasaccharide. For additional validation, calibration curves were constructed using individual calibrators as the reference method as well as the HDHF method. Several low molecular weight heparins were profiled for their molecular weight using these methods. In comparison to the reference method, the molecular weights obtained with the HDHF method were 25-40% higher. When the results were recalculated assuming the molecular weight of the second to the last peak as 1.2 kDa, the HDHF results compared well with the reference method. Additionally, it is seen that the HDHF method does not identify molecular components greater than 8.0 kDa.
Calibration↗
Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma.
Rhabdomyosarcoma (RMS) is a highly malignant tumor that is histologically related to skeletal muscle, yet genetic and molecular lesions underlying its genesis and progression remain largely unknown. In this study we have compared the molecular profiles of two different mouse models of RMS, each associated with a defined primary genetic defect known to play a role in rhabdomyosarcomagenesis in man. We report that RMS of heterozygous Patched1 (Ptch1) mice show less aggressive growth and a greater degree of differentiation than RMS of heterozygous p53 mice. By means of cDNA microarray analysis we demonstrate that RMS in Ptch1 mutants predominantly express a number of myogenic markers, including myogenic differentiation 1, myosin heavy chain, actin, troponin and tropomyosin, as well as genes associated with Hedgehog/Patched signaling like insulin-like growth factor 2, forkhead box gene Foxf1 and the growth arrest and DNA-damage-inducible gene Gadd45a. In sharp contrast, RMS in p53 mutants display higher expression levels of cell cycle-associated genes like cyclin B1, cyclin-dependent kinase 4 and the proliferation marker Ki-67. These results demonstrate that different causative mutations lead to distinct gene expression profiles in RMS, which appear to reflect their different biological characteristics. Our results provide a first step towards a molecular classification of different forms of RMS. If the described differences can be confirmed in human RMS our results will contribute to a new molecular taxonomy of this cancer, which will be critical for gene mutation- and expression-specific therapy.
Alleles↗
Validation of the European Pharmacopeial method for molecular weight profiling of low molecular weight heparins: comparative studies utilizing an improved calibrator, ITH-3.
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Calibration↗
Molecular characterization of Enterococcus faecium isolated from hospitalized patients in Korea.
AIMS: Multilocus sequence typing (MLST) was performed for vancomycin-resistant Enterococcus faecium (VREF) from diverse geographical areas in Korea to obtain insights into the genetic relationships with other molecular profiles. To understand the diversity of lineages, vancomycin-susceptible E. faecium (VSEF) were included. METHODS AND RESULTS: A total of 60 E. faecium isolates were analysed by MLST and esp profile. Molecular typing of Tn1546 of 30 VREF strains was evaluated by overlapping PCR of Tn1546 and DNA sequencing. Seven sequence types (ST) were found among 30 VSEF isolates, and four STs were found among 30 VREF isolates. The types most frequently encountered were ST 78 (26 isolates) and ST 203 (16 isolates). Of the 60 E. faecium isolates, 35 isolates were positive for the esp gene. On molecular typing of Tn1546, all VREF isolates were divided into four main types. Strains with the same ST showed divergence in Tn1546 types and strains with the same Tn1546 type represented different STs. CONCLUSIONS: An association between Tn1546 typing and MLST was not found. SIGNIFICANCE AND IMPACT OF THE STUDY: These results suggest that the horizontal spread of Tn1546 between strains plays a major role in the dissemination of vancomycin resistance in Korea.
Bacterial Typing Techniques↗
Biochemical and pharmacologic profile of low molecular weight heparin (LU 47311, Clivarin).
1. Clivarin is a homogeneous LMWH as determined by the data obtained in molecular profiling studies. 2. The limited biochemical studies carried out indicated that this LMWH has a specific potency of 124 anti-Xa IU/mg and a weaker APTT activity of approximately 30 U/mg. 3. Assay-dependent neutralization of the in vitro effects of Clivarin was noted. Protamine preparations at equigravimetric concentrations effectively neutralized the APTT and TT effects; however, Heptest and anti-Xa effects were only partially neutralized. In contrast, heparin's effects were completely neutralized by this agent. 4. PF 4 only partially neutralized the effects of Clivarin. Assay-dependent variations were noted in this study. 5. In comparison to heparin, the hemorrhagic effects of Clivarin were much weaker. 6. Clivarin produced a dosage-dependent antithrombotic action in both the intravenous and subcutaneous studies. This agent also showed sustained activity and better bioavailability characteristics than heparin. 7. Clivarin exhibited a distinct biochemical and pharmacologic profile that may be useful in the optimization of this agent.
Animals↗
Predicting risk of breast cancer recurrence using gene-expression profiling.
The molecular profiling of breast tumors using the powerful microarray technology has uncovered the molecular heterogeneity of breast tumors and has offered novel insight into breast tumorigenesis. The estrogen receptor (ER) has been shown to be the most important discriminator dichotomizing breast cancer into two main subsets. At the same time, proliferation, as captured by the recently developed Genomic Grade Index (GGI) has been found to be the most important prognostic factor in breast cancer, far beyond ER status. Interestingly, this index encompasses a significant portion of the predictive power of many published prognostic signatures. The challenge now is to integrate all the prognostic gene signatures available to date towards a comprehensive genomic fingerprint of the primary tumor. In the future, we should be able to offer individualized treatment to our patients based on a clinical decision-making algorithm that takes into account the clinicopathological parameters, the genomic profile of the primary tumor, the presence of micrometastatic cells and pharmacogenetic data for drug response.
Animals↗
Molecular tumor profiling: translating genomic insights into clinical advances.
Molecular profiling of the transcripts or proteins within an individual tumor may in future provide important prognostic and therapeutic clinical information both for the affected individual and for their extended family, but for the time being traditional genetics and pathology retain their place in the clinic.
Breast Neoplasms↗