FGR

Gene Summary

Gene:FGR; FGR proto-oncogene, Src family tyrosine kinase
Aliases: SRC2, c-fgr, c-src2, p55-Fgr, p58-Fgr, p55c-fgr, p58c-fgr
Location:1p35.3
Summary:This gene is a member of the Src family of protein tyrosine kinases (PTKs). The encoded protein contains N-terminal sites for myristylation and palmitylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. The protein localizes to plasma membrane ruffles, and functions as a negative regulator of cell migration and adhesion triggered by the beta-2 integrin signal transduction pathway. Infection with Epstein-Barr virus results in the overexpression of this gene. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tyrosine-protein kinase Fgr
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
Show (32)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Chromosome Aberrations
  • Herpesvirus 4, Human
  • RTPCR
  • Proto-Oncogene Proteins c-myc
  • Cancer Gene Expression Regulation
  • Cancer DNA
  • Transcription
  • Gene Expression
  • Protein-Tyrosine Kinases
  • Chromosome 1
  • Nucleic Acid Hybridization
  • FGR
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Genetic Markers
  • Epstein-Barr Virus Nuclear Antigens
  • Northern Blotting
  • Phorbol Esters
  • Proto-Oncogenes
  • Biomarkers, Tumor
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Polymerase Chain Reaction
  • Drug Resistance
  • Oncogenes
  • Messenger RNA
  • Burkitt Lymphoma
  • B-Lymphocytes
  • Oncogene Proteins
  • Antineoplastic Agents
  • Restriction Mapping
  • Gene Expression Profiling
  • Translocation
  • Cell Line
  • Breast Cancer
  • Cell Differentiation
  • Gene Amplification
  • Neoplasm Proteins
  • Tumor Virus Infections
  • Karyotyping
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FGR (cancer-related)

Verheecke M, Cortès Calabuig A, Finalet Ferreiro J, et al.
Genetic and microscopic assessment of the human chemotherapy-exposed placenta reveals possible pathways contributive to fetal growth restriction.
Placenta. 2018; 64:61-70 [PubMed] Related Publications
INTRODUCTION: Fetal growth restriction (FGR) carries an increased risk of perinatal mortality and morbidity. A major cause of FGR is placental insufficiency. After in utero chemotherapy-exposure, an increased incidence of FGR has been reported. In a prospective cohort study we aimed to explore which pathways may contribute to chemotherapy-associated FGR.
METHODS: Placental biopsies were collected from 25 cancer patients treated with chemotherapy during pregnancy, and from 66 control patients. Differentially expressed pathways between chemotherapy-exposed patients and controls were examined by whole transcriptome shotgun sequencing (WTSS) and Ingenuity Pathway Analysis (IPA). Immunohistochemical studies for 8-OHdG and eNOS (oxidative DNA damage), proliferation (PCNA) and apoptosis (Cleaved Caspase 3) were performed. The expression level of eNOS, PCNA and IGFBP6 was verified by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR).
RESULTS: Most differential expressed genes between chemotherapy-exposed patients and controls were related to growth, developmental processes, and radical scavenging networks. The duration of chemotherapy exposure had an additional impact on the expression of genes related to the superoxide radicals degeneration network. Immunohistochemical analyses showed a significantly increased expression of 8-OHdG (P = 0.003) and a decreased expression of eNOS (P=0.015) in the syncytiotrophoblast of the placenta of cancer patients. A decreased expression of PCNA was detected by immunohistochemistry as RT-qPCR (NS).
CONCLUSION: Chemotherapy exposure during pregnancy results in an increase of oxidative DNA damage and might impact the placental cellular growth and development, resulting in an increased incidence of FGR in this specific population. Further large prospective cohort studies and longitudinal statistical analyses are needed.

Zhang C, Sun Q
Weighted gene co-expression network analysis of gene modules for the prognosis of esophageal cancer.
J Huazhong Univ Sci Technolog Med Sci. 2017; 37(3):319-325 [PubMed] Related Publications
Esophageal cancer is a common malignant tumor, whose pathogenesis and prognosis factors are not fully understood. This study aimed to discover the gene clusters that have similar functions and can be used to predict the prognosis of esophageal cancer. The matched microarray and RNA sequencing data of 185 patients with esophageal cancer were downloaded from The Cancer Genome Atlas (TCGA), and gene co-expression networks were built without distinguishing between squamous carcinoma and adenocarcinoma. The result showed that 12 modules were associated with one or more survival data such as recurrence status, recurrence time, vital status or vital time. Furthermore, survival analysis showed that 5 out of the 12 modules were related to progression-free survival (PFS) or overall survival (OS). As the most important module, the midnight blue module with 82 genes was related to PFS, apart from the patient age, tumor grade, primary treatment success, and duration of smoking and tumor histological type. Gene ontology enrichment analysis revealed that "glycoprotein binding" was the top enriched function of midnight blue module genes. Additionally, the blue module was the exclusive gene clusters related to OS. Platelet activating factor receptor (PTAFR) and feline Gardner-Rasheed (FGR) were the top hub genes in both modeling datasets and the STRING protein interaction database. In conclusion, our study provides novel insights into the prognosis-associated genes and screens out candidate biomarkers for esophageal cancer.

Sunami Y, Araki M, Kan S, et al.
Histone Acetyltransferase p300/CREB-binding Protein-associated Factor (PCAF) Is Required for All-
J Biol Chem. 2017; 292(7):2815-2829 [PubMed] Free Access to Full Article Related Publications
Differentiation therapy with all-

Joosten M, Ginzel S, Blex C, et al.
A novel approach to detect resistance mechanisms reveals FGR as a factor mediating HDAC inhibitor SAHA resistance in B-cell lymphoma.
Mol Oncol. 2016; 10(8):1232-44 [PubMed] Free Access to Full Article Related Publications
Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) are not commonly used in clinical practice for treatment of B-cell lymphomas, although a subset of patients with refractory or relapsed B-cell lymphoma achieved partial or complete remissions. Therefore, the purpose of this study was to identify molecular features that predict the response of B-cell lymphomas to SAHA treatment. We designed an integrative approach combining drug efficacy testing with exome and captured target analysis (DETECT). In this study, we tested SAHA sensitivity in 26 B-cell lymphoma cell lines and determined SAHA-interacting proteins in SAHA resistant and sensitive cell lines employing a SAHA capture compound (CC) and mass spectrometry (CCMS). In addition, we performed exome mutation analysis. Candidate validation was done by expression analysis and knock-out experiments. An integrated network analysis revealed that the Src tyrosine kinase Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog (FGR) is associated with SAHA resistance. FGR was specifically captured by the SAHA-CC in resistant cells. In line with this observation, we found that FGR expression was significantly higher in SAHA resistant cell lines. As functional proof, CRISPR/Cas9 mediated FGR knock-out in resistant cells increased SAHA sensitivity. In silico analysis of B-cell lymphoma samples (n = 1200) showed a wide range of FGR expression indicating that FGR expression might help to stratify patients, which clinically benefit from SAHA therapy. In conclusion, our comprehensive analysis of SAHA-interacting proteins highlights FGR as a factor involved in SAHA resistance in B-cell lymphoma.

Cho HJ, Kim SS, Wang HJ, et al.
Detection of Novel Genomic Markers for Predicting Prognosis in Hepatocellular Carcinoma Patients by Integrative Analysis of Copy Number Aberrations and Gene Expression Profiles: Results from a Long-Term Follow-Up.
DNA Cell Biol. 2016; 35(2):71-80 [PubMed] Related Publications
The aim of this study was to explore novel genomic biomarkers predicting hepatocellular carcinoma (HCC) prognosis by integrative analysis of DNA copy number aberrations (CNAs) and gene expression profiles. Array comparative genomic hybridization and expression array were performed on 45 and 31 HCC samples, respectively. To identify functionally important genes, concordant results of DNA copy number and gene expression were retrieved by integrative analysis. Cox regression analysis indicated that the CNAs in 192 genomic regions were significantly associated with overall survival (OS; p < 0.05). Integrative analysis capturing concordant results demonstrated that the low expression of TLE4 (p = 0.041) and XPA (p = 0.006) was associated with poor OS. In the analysis of tumor recurrence, 514 genomic regions with CNAs were associated with recurrence. Integrative analysis revealed that the overexpression of 16 genes, including FGR (p = 0.003), RELA (p = 0.049), LTBP3 (p = 0.050), and RIN1 (p = 0.023), was significantly associated with shorter time to tumor recurrence. On multivariate analysis, FGR and XPA were independent risk factors of early recurrence and poor OS, respectively. Integrated analysis of CNAs and gene expression profiles correlated with long-term follow-up data successfully identified potential prognostic markers predicting survival and tumor recurrence in patients with HCC who underwent surgical resection.

Nilsson EM, Laursen KB, Whitchurch J, et al.
MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators.
Oncotarget. 2015; 6(34):35710-25 [PubMed] Free Access to Full Article Related Publications
Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expression of AR coregulators is implicated in cancer. We have shown that over-expression of KDM1A, an AR coregulator, contributes to PCa recurrence by promoting VEGFA expression. However the mechanism(s) whereby AR coregulators are increased in PCa remain poorly understood. In this study we show that the microRNA hsa-miR-137 (miR137) tumor suppressor regulates expression of an extended network of transcriptional coregulators including KDM1A/LSD1/AOF1, KDM2A/JHDM1A/FBXL11, KDM4A/JMJD2A, KDM5B JARID1B/PLU1, KDM7A/JHDM1D/PHF8, MED1/TRAP220/DRIP205 and NCoA2/SRC2/TIF2. We show that expression of miR137 is increased by androgen in LnCaP androgen PCa responsive cells and that the miR137 locus is epigenetically silenced in androgen LnCaP:C4-2 and PC3 independent PCa cells. In addition, we found that restoration of miR137 expression down-regulates expression of VEGFA, an AR target gene, which suggests a role of miR137 loss also in cancer angiogenesis. Finally we show functional inhibition of miR137 function enhanced androgen induction of PSA/KLK3 expression. Our data indicate that miR137 functions as an androgen regulated suppressor of androgen signaling by modulating expression of an extended network of transcriptional coregulators. Therefore, we propose that epigenetic silencing of miR137 is an important event in promoting androgen signaling during prostate carcinogenesis and progression.

Suh JH, Chattopadhyay A, Sieglaff DH, et al.
Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists.
PLoS One. 2015; 10(9):e0137103 [PubMed] Free Access to Full Article Related Publications
The androgen receptor (AR) surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC) cells. These effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared MJC13 and classic AR antagonists such as flutamide and bicalutamide. Microarray analysis and confirmatory qRT-PCR reveals that MJC13 and flutamide inhibit dihydrotestosterone (DHT)-dependent genes in LNCaP PC cells. Both compounds are equally effective on a genome wide basis and as effective as second generation AR antagonists (MDV3100, ARN-509) at selected genes. MJC13 inhibits AR binding to the prostate specific antigen (PSA) promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects castrate resistant prostate cancer (CRPC) reveals that it inhibits flutamide activation of an AR mutant (ART877A) that emerges during flutamide withdrawal syndrome, but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR), which can co-opt androgen-dependent signaling networks in CRPC. Importantly, MJC13 inhibits AR interactions with SRC2 and β-catenin in the nucleus and, unlike flutamide, strongly inhibits amplification of AR activity obtained with transfected SRC2 and β-catenin. MJC13 also inhibits DHT and β-catenin-enhanced cell division in LNCaP cells. Thus, a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in particular forms of CRPC.

Bunaciu RP, Jensen HA, MacDonald RJ, et al.
6-Formylindolo(3,2-b)Carbazole (FICZ) Modulates the Signalsome Responsible for RA-Induced Differentiation of HL-60 Myeloblastic Leukemia Cells.
PLoS One. 2015; 10(8):e0135668 [PubMed] Free Access to Full Article Related Publications
6-Formylindolo(3,2-b)carbazole (FICZ) is a photoproduct of tryptophan and an endogenous high affinity ligand for aryl hydrocarbon receptor (AhR). It was previously reported that, in patient-derived HL-60 myeloblastic leukemia cells, retinoic acid (RA)-induced differentiation is driven by a signalsome containing c-Cbl and AhR. FICZ enhances RA-induced differentiation, assessed by expression of the membrane differentiation markers CD38 and CD11b, cell cycle arrest and the functional differentiation marker, inducible oxidative metabolism. Moreover, FICZ augments the expression of a number of the members of the RA-induced signalsome, such as c-Cbl, Vav1, Slp76, PI3K, and the Src family kinases Fgr and Lyn. Pursuing the molecular signaling responsible for RA-induced differentiation, we characterized, using FRET and clustering analysis, associations of key molecules thought to drive differentiation. Here we report that, assayed by FRET, AhR interacts with c-Cbl upon FICZ plus RA-induced differentiation, whereas AhR constitutively interacts with Cbl-b. Moreover, correlation analysis based on the flow cytometric assessment of differentiation markers and western blot detection of signaling factors reveal that Cbl-b, p-p38α and pT390-GSK3β, are not correlated with other known RA-induced signaling components or with a phenotypic outcome. We note that FICZ plus RA elicited signaling responses that were not typical of RA alone, but may represent alternative differentiation-driving pathways. In clusters of signaling molecules seminal to cell differentiation, FICZ co-administered with RA augments type and intensity of the dynamic changes induced by RA. Our data suggest relevance for FICZ in differentiation-induction therapy. The mechanism of action includes modulation of a SFK and MAPK centered signalsome and c-Cbl-AhR association.

Chen M, Gan X, Deng L, Hotta H
The NS5A protein of hepatitis C virus transcriptionally upregulates the AGR3 gene expression.
Kobe J Med Sci. 2015; 61(1):E27-35 [PubMed] Related Publications
The non-structural protein 5A (NS5A) of hepatitis C virus (HCV) is a multifunctional protein involved in the HCV lifecycle and pathogenesis. The precise molecular mechanisms of NS5A-mediated pathogenesis still remain to be clarified. In this study, we performed cDNA microarray analysis on NS5A-expressing HEK293 cells and the non-expressing control to screen the possible cellular genes dysregulated by NS5A. Subsequent quantitative real time PCR (qRT-PCR) analysis on NS5A-expressing cells and the control confirmed that NS5A upregulated the anterior gradient homolog 3 (AGR3) mRNA expression. The domain III of NS5A was responsible for the activation of AGR3 gene expression. AGR3 mRNA expression levels were upregulated also in Huh7.5 cells harboring a full-genome HCV-1b RNA replicon (FGR) and in those infected with HCV-2a. Moreover, AGR3 promoter activity was activated in NS5A-expressing cells, FGR-harboring cells and HCV-infected cells. Taken together, our present results suggest that HCV NS5A transcriptionally activates the cancer-associated AGR3 gene. This may be a novel mechanism of HCV-mediated pathogenesis, especially hepatocarcinogenesis.

Iżykowska K, Zawada M, Nowicka K, et al.
Submicroscopic genomic rearrangements change gene expression in T-cell large granular lymphocyte leukemia.
Eur J Haematol. 2014; 93(2):143-9 [PubMed] Related Publications
OBJECTIVES: To better understand the molecular pathogenesis of T-cell large granular lymphocyte leukemia (T-LGL), we decided to search for those genetic alterations in T-LGL patients and MOTN-1 cell line (established from T-LGL patient) that have an impact on gene expression and as a result can influence cell biology.
METHODS: Multicolor fluorescence in situ hybridization (mFISH) analysis of the MOTN-1 cell line was performed as well as paired-end next-generation sequencing (NGS; Illumina HiSeq2000) of this cell line and one T-LGL patient. In addition, chosen 6q region was characterized in three T-LGL patients using high-resolution comparative genomic hybridization (FT-CGH) and LM-PCR. Gene expression was studied by RNA sequencing (RNAseq; SOLID5500).
RESULTS: Rearrangements were detected within 1p and 2q in MOTN-1 affecting expression of FGR, ZEB2, and CASP8, and within 6q in MOTN-1 and one T-LGL patient affecting MAP3K5 and IFNGR1. Nineteen genes, among them FOXN3, RIN3, AKT1, PPP2R5C, were overexpressed as a result of an amplification in 14q in one T-LGL patient. Two novel fusion transcripts were identified: CASP8-ERBB4 in MOTN-1 and SBF1-PKHD1L1 in T-LGL patient.
CONCLUSIONS: This study showed that submicroscopic genomic rearrangements change gene expression in T-LGL. Several genes involved in rearrangements were previously linked to cancer and survival pattern that characterizes T-LGL cells.

Jensen HA, Styskal LE, Tasseff R, et al.
The Src-family kinase inhibitor PP2 rescues inducible differentiation events in emergent retinoic acid-resistant myeloblastic leukemia cells.
PLoS One. 2013; 8(3):e58621 [PubMed] Free Access to Full Article Related Publications
Retinoic acid is an embryonic morphogen and dietary factor that demonstrates chemotherapeutic efficacy in inducing maturation in leukemia cells. Using HL60 model human myeloid leukemia cells, where all-trans retinoic acid (RA) induces granulocytic differentiation, we developed two emergent RA-resistant HL60 cell lines which are characterized by loss of RA-inducible G1/G0 arrest, CD11b expression, inducible oxidative metabolism and p47(phox) expression. However, RA-treated RA-resistant HL60 continue to exhibit sustained MEK/ERK activation, and one of the two sequentially emergent resistant lines retains RA-inducible CD38 expression. Other signaling events that define the wild-type (WT) response are compromised, including c-Raf phosphorylation and increased expression of c-Cbl, Vav1, and the Src-family kinases (SFKs) Lyn and Fgr. As shown previously in WT HL60 cells, we found that the SFK inhibitor PP2 significantly increases G1/G0 cell cycle arrest, CD38 and CD11b expression, c-Raf phosphorylation and expression of the aforementioned regulators in RA-resistant HL60. The resistant cells were potentially incapable of developing inducible oxidative metabolism. These results motivate the concept that RA resistance can occur in steps, wherein growth arrest and other differentiation events may be recovered in both emergent lines. Investigating the mechanistic anomalies in resistant cell lines is of therapeutic significance and helps to mechanistically understand the response to retinoic acid's biological effects in WT HL60 cells.

Haenisch B, Huber M, Wilhelm T, et al.
Investigation into mechanisms mediating the inhibitory effect of 1,4-benzodiazepines on mast cells by gene expression profiling.
Life Sci. 2013; 92(6-7):345-51 [PubMed] Related Publications
AIMS: This study aims to identify by a molecular genetic approach potential targets in mast cells at which 1,4-benzodiazepines may cause their inhibitory effect on mast cell activity.
MAIN METHODS: Gene expression analyses with microarray gene chip and/or quantitative PCR were performed using 1,4-benzodiazepine-treated human mast cell leukemia HMC-1.2 cells, promyelocytic leukemia HL-60 cells and human mast cells from healthy volunteers and patients with mast cell activation disease (MCAD). Pathway analysis was applied to search for enriched biological functions and canonical pathways within differentially regulated genes.
KEY FINDINGS: Both neoplastic and normal human mast cells express several GABA(A) receptor subunits at the mRNA level. In mast cells from MCAD patients expression of some GABA(A) receptor subunits and expression of the translocator protein TSPO are increased compared with those from healthy controls. Expression of the protein tyrosine kinases Lyn, Fgr and Yes1 was increased in HMC-1.2 cells as compared with the ontogenetically related HL60 cells. Differences in gene regulation in HMC-1.2 cells after treatment with the 1,4-benzodiazepines clonazepam, flunitrazepam and 4-chlorodiazepam suggested that signaling and gene expression induced by clonazepam was similar to that of flunitrazepam but different from that of 4-chlorodiazepam. This conclusion is supported by the results of the pathway analysis.
SIGNIFICANCE: A novel type of GABA(A) receptors on mast cells appears to be involved in the inhibition of mast cell activity by 1,4-benzodiazepines. These receptors seem to be composed without γ subunits suggesting unique pharmacological properties. An action at Src-kinases, or at TSPO located in the plasma membrane may also be involved.

Szczepanek J, Pogorzala M, Jarzab M, et al.
Expression profiles of signal transduction genes in ex vivo drug-resistant pediatric acute lymphoblastic leukemia.
Anticancer Res. 2012; 32(2):503-6 [PubMed] Related Publications
AIM: Identification of signal transduction genes related to drug resistance in pediatric acute lymphoblastic leukemia (ALL).
MATERIALS AND METHODS: Ex vivo drug resistance in 107 children, divided into study and validation groups, was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) drug resistance assay. The gene expression profile was identified by microarray analysis and validated by quantitative reverse transcription polymerase chain reaction.
RESULTS: A set of five genes involved in signal transduction, present in each resistance profile, was identified. The expression of four genes was up-regulated: Gardner-Rasheed feline sarcoma viral oncogene homolog, v-Fgr (FGR), S100 calcium binding protein A11 (S100A11), formyl peptide receptor 1 (FPR1), ArfGAP with RhoGAP domain, ankyrin repeat and PH1 domain (ARAP1), while the expression of growth hormone 1 (GH1) was found to be down-regulated in resistant leukemia blasts.
CONCLUSION: Ex vivo exposure of leukemia cells to anticancer drugs induces changes in the expression of genes involved in cell signaling pathways. These genes play an important role in the mechanism of cellular drug resistance.

Tesser-Gamba F, Petrilli AS, de Seixas Alves MT, et al.
MAPK7 and MAP2K4 as prognostic markers in osteosarcoma.
Hum Pathol. 2012; 43(7):994-1002 [PubMed] Related Publications
Osteosarcoma is a class of cancer originating from the bone, affecting mainly children and young adults. Cytogenetic studies showed the presence of rearrangements and recurrent gains in specific chromosomal regions, indicating the possible involvement of genes located in these regions during the pathogenesis of osteosarcoma. These studies investigated expression of 10 genes located in the chromosomal region involved in abnormalities in osteosarcoma, 1p36, 17p, and chromosome 19. The purpose of this study was to investigate the expression profile of genes located in regions involved in chromosomal rearrangements in osteosarcoma. We used quantitative real-time polymerase chain reaction to investigate the expression of 10 genes located in 1p36.3 (MTHFR, ERRFI1, FGR, E2F2), 17p (MAPK7, MAP2K4), and chromosome 19 (BBC3, FOSB, JUND, and RRAS), in 70 samples taken from 30 patients (30 prechemotherapy, 30 postchemotherapy, and 10 metastases specimens) and 10 healthy bones as a control sample. The most interesting results showed a strong association between the expression levels of MAPK7 and MAP2K4 genes and clinical parameters of osteosarcoma. Overexpression of these genes was significantly associated to a poor response to treatment (P = .0001 and P = .0049, respectively), tumor progression, and worse overall survival (P = .0052 and P = .0085, respectively), suggesting that MAPK7 and MAP2K4 could play an important role in osteosarcoma tumorigenesis. Thus, these genes could be good markers in assessing response to treatment and development of osteosarcoma.

Zwart W, Theodorou V, Kok M, et al.
Oestrogen receptor-co-factor-chromatin specificity in the transcriptional regulation of breast cancer.
EMBO J. 2011; 30(23):4764-76 [PubMed] Free Access to Full Article Related Publications
The complexity of oestrogen receptor α (ERα)-mediated transcription is becoming apparent, but global insight into the co-regulatory proteins that assist ERα transcription is incomplete. Here, we present the most comprehensive chromatin-binding landscape of ERα co-regulatory proteins to date. We map by ChIP-seq the essential p160 co-regulators (SRC1, SRC2 and SRC3), and the histone acetyl transferases p300 and CBP in MCF-7 breast cancer cells. We find a complex network of co-regulator binding, with preferential binding sites for each co-regulator. Unlike previous suggestions, we find SRC recruitment almost exclusively following ligand treatment. Interestingly, we find specific subsets of genes regulated by ligand-dependent and -independent co-regulator recruitment. Co-factor-binding profiles were integrated with expression data from cell lines and primary tumour cohorts, to reveal specific transcriptional networks that influence clinical outcome. Genes that are bound by SRC3, but not other p160 proteins, have predictive value in cohorts of breast cancer patients. By generating a robust and global view of co-factor-binding properties, we discover new levels of co-regulator complexity, but also reveal specific gene networks that may influence endocrine response.

Jasinski P, Zwolak P, Terai K, et al.
MT477 acts in tumor cells as an AURKA inhibitor and strongly induces NRF-2 signaling.
Anticancer Res. 2011; 31(4):1181-7 [PubMed] Related Publications
BACKGROUND: The novel compound thiopyrano [2,3-c]quinoline (MT477) has been shown to exhibit antitumor activity in both in vitro and in vivo studies. The present study examined the expression levels of 10,000 genes and how they changed after MT477 treatment in three cancer cell lines: H226, MDA231 and MiaPaCa-2. Materials and Methods/
RESULTS: Molecular function analysis revealed changes in genes involved in cell death, cell-cycle progression and cellular growth and proliferation in all three cancer cell lines. Canonical pathway analysis showed the involvement of the NRF2-mediated oxidative stress response, glucocorticoid, p53, RXR-VDR, G(1)/S checkpoint regulation, ERK, SAPK/JNK and JAS/Stat signaling. Analysis of 234 kinases and phosphatases using a kinase inhibition assay demonstrated a strong inhibitory effect for MAPK14 (104 ± 2%), AMPK A2/B1/G1 (89%) and FGR (83 ± 2%). AURKA was inhibited at 77 ± 1%. MiaPaCa-2 tumor xenograft studies showed a 49.5 ±1 4.8% inhibitory effect in mice treated with 100 μg/kg MT477 compared to untreated mice (p=0.0021).
CONCLUSION: MT477 induces molecular mechanisms related to cell death, survival, and inhibition of cellular growth in vitro and in vivo.

Prabhu JS, Korlimarla A, Banerjee A, et al.
Gene-specific methylation: potential markers for colorectal cancer.
Int J Biol Markers. 2009 Jan-Mar; 24(1):57-62 [PubMed] Related Publications
PURPOSE: Aberrant methylation of the promoter region is associated with silencing of many genes in neoplasia. CpG island methylation is an epigenetic mechanism for transcriptional silencing that occurs at various stages of colon tumorigenesis. In this study, we tested the promoter methylation and expression of seven genes from various pathways of DNA repair, apoptosis and inflammation, i.e., sFRP1, MLH1, RASSF1A, CDA, v-fgr, LYN-B, and TNFR10d.
METHOD: The genes were analyzed by quantitative polymerase chain reaction for the level of gene expression. The promoter methylation status of the genes was studied by methylation-specific polymerase chain reaction.
RESULT: The correlation of promoter methylation status with suppressed gene expression patterns suggested a potential role for the silencing these genes in colon cancer progression.
CONCLUSION: Promoter methylations of the studied genes could be explored as promising biomarkers for new diagnostic, prognostic and therapeutic targets of colorectal cancer.

Brusa G, Zuffa E, Hattinger CM, et al.
Genomic imbalances associated with secondary acute leukemias in Hodgkin lymphoma.
Oncol Rep. 2007; 18(6):1427-34 [PubMed] Related Publications
Secondary tumors and leukemias are major complications in Hodgkin lymphoma (HL). They likely arise from clonal selection of cells that have accumulated genomic lesions induced by chemo- and radiotherapy and may be further promoted by the loss of DNA repair and/or other pathways ensuring the fidelity of replicated DNA. To distinguish genomic imbalances associated with the development of acute myeloid leukemia (AML) in HL we used an array-based comparative genomic hybridization (aCGH) strategy on whole lymph node biopsies of HL patient. Genomic imbalances (amplifications and deletions) associated with AML outcome in 3 classic HL patients, at clinical diagnosis they exhibited a discrete individual variability. Three amplifications and 5 deletions were shared by all 3 patients. They involved AFM137XA11, a 9p11.2 pericentric region; FGFR1, the FGF receptor most frequently translocated in AML; PPARBP, a co-activator of nuclear receptors RARalpha, RXR and TRbeta1; AFM217YD10, a 17q25 telomeric region; FGR, an SRC2 kinase involved in cytokine production by NK and CD4+ NKT cells; GATA3, a Th2-specific transcription factor; TOP1, involved in DNA recombination and repair; WT1, a transcription factor involved in CD8+ T cell response against leukaemic blasts. Immunohistochemistry confirmed aCGH results and distinguished the distribution of either amplified or deleted gene products in neoplastic Reed Sternberg (RS) cells and non-neoplastic lymph node components.

Tan JM, Chow VT
Cellular expression, localization and interactions of the product of the human MOST-1 gene associated with breast and prostate cancers.
Int J Oncol. 2007; 30(1):81-9 [PubMed] Related Publications
We previously isolated and characterized the novel human gene MOST-1 (C8orf17) that is ubiquitously expressed in all cancer cell lines tested but differentially expressed in normal adult tissues. MOST-1 maps to chromosome region 8q24.2 whose amplification is frequently associated with breast and prostate cancers. RT-PCR analyses of breast and prostatic biopsies revealed MOST-1 overexpression and/or amplification in high-grade carcinomas. We raised and characterized a polyclonal antibody against a MOST-1-specific synthetic peptide. in vitro expression of MOST-1 protein revealed a tendency to exist as high molecular mass isoforms which are SDS-insoluble upon thermal stress. MOST-1 displayed cytoplasmic localization in four human cell lines (hTERT-HME1 normal mammary epithelial, MCF7 breast adenocarcinoma, PrEC normal prostate epithelial and DU145 prostate carcinoma), with polar expression during cell division. Knockdown of MOST-1 expression in DU145 cells resulted in reduced cell proliferation but enhanced apoptosis implying a putative mitogenic role of MOST-1. Yeast two-hybrid analyses demonstrated interaction with seven human proteins, most of which are overexpressed in tumors or involved in metabolic pathways. The interacting proteins were creatine kinase, Gardner feline sarcoma v-FGR oncogene product, telethonin, SNC73 protein, ferritin light chain, peripheral benzodiazepine receptor, and immunoglobulin C (mu) and C (delta) heavy chain. Co-immunoprecipitation assays validated the interactions of MOST-1 with the latter three proteins. Our results suggest that MOST-1 is associated with cell survival, proliferation and progression of cancer cells.

Valladares A, Hernández NG, Gómez FS, et al.
Genetic expression profiles and chromosomal alterations in sporadic breast cancer in Mexican women.
Cancer Genet Cytogenet. 2006; 170(2):147-51 [PubMed] Related Publications
Breast cancer is the second-leading cause of death among Mexican women >35 years of age. At the molecular level, changes in many genetic pathways have been reported to be associated with this neoplasm. To analyze these changes, we determined gene expression profiles and chromosomal structural alterations in tumors from Mexican women. We obtained mRNA to identify expression profiles with microarray technology, and DNA to determine amplifications and deletions, in 10 fresh sporadic breast tumor biopsies without treatment, as well as in 10 nonaffected breast tissues. Expression profiles were compared with genetic changes observed by comparative genomic hybridization (CGH). We compared the expression profiles against the structural alterations from the studied genes by means of microarrays; at least 17 of these genes correlated with DNA copy number alterations. We found that the following genes were overexpressed: LAMC1, PCTK3, CCNC, CCND1, FGF3, PCTK2, L1CAM, BGN, and PLXNB3 (alias PLEXR). Underexpressed genes included CASP9, FGR, TP73, HSPG2, and ERCC1; genes turned off included FRAP1, EPHA2 (previously ECK), IL12A, E2F5, TNFRSF10B, TNFRSF10A, EFNB3, and BCL2. The results will allow us, in the near future, to outline genes that could serve as diagnostic, prognostic, or target therapy markers for the Mexican population.

Martínez-Jiménez CP, Gómez-Lechón MJ, Castell JV, Jover R
Underexpressed coactivators PGC1alpha and SRC1 impair hepatocyte nuclear factor 4 alpha function and promote dedifferentiation in human hepatoma cells.
J Biol Chem. 2006; 281(40):29840-9 [PubMed] Related Publications
Hepatocyte nuclear factor 4alpha (HNF4alpha) plays critical roles during liver development and in the transcriptional regulation of many hepatic genes in adult liver. Here we have demonstrated that in human hepatoma HepG2 cells, HNF4alpha is expressed at levels as high as in human liver but its activity on target genes is very low or absent. We have discovered that the low expression of key coactivators (PGC1alpha, SRC1, SRC2, and PCAF) might account for the lack of function of HNF4alpha in HepG2 cells. Among them, PGC1alpha and SRC1 are the two most important HNF4alpha coactivators as revealed by reporter assays with an Apo-CIII promoter construct. Moreover, the expression of these two coactivators was found to be down-regulated in all human hepatomas investigated. Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. The positive effect of PGC1alpha was seen to be dependent on HNF4alpha. Finally, insulin treatment of human hepatocytes and HepG2 cells caused repression of PGC1alpha and a concomitant down-regulation of ApoCIII, PEPCK, AldoB, and OTC. Altogether, our results suggest that SRC1, and notably PGC1alpha, are key coactivators for the proper function of HNF4alpha in human liver and for an integrative control of multiple hepatic genes involved in metabolism and homeostasis. The down-regulation of key HNF4alpha coactivators could be a determinant factor for the dedifferentiation of human hepatomas.

O'Toole SA, Dunn E, Sheppard BL, et al.
Genome-wide analysis of deoxyribonucleic acid in endometrial cancer using comparative genomic hybridization microarrays.
Int J Gynecol Cancer. 2006 Mar-Apr; 16(2):834-42 [PubMed] Related Publications
The aim of this study was to identify amplified oncogenes in endometrial cancer using array-based comparative genomic hybridization (array CGH). Despite its prevalence, the molecular mechanisms of endometrial carcinogenesis are still poorly understood. The selected array CGH allows the simultaneous examination of 58 oncogenes commonly amplified in human cancers and is capable of achieving increased mapping resolution compared with conventional CGH. A subset of 8 specimens from a bank of 60 malignant and normal specimens was selected for array analysis to identify potential genes of interest. TaqMan polymerase chain reaction was carried out on the 60 specimens to examine if aberrations at the genomic level correlated with gene expression and to compare expression in normal and malignant samples. Oncogenes amplified in the endometrial cancers included AR, PIK3CA, MET, HRAS, NRAS, D17S1670, FGFR1, CTSB, RPS6KB1, LAMC2, MYC, PDGFRA, FGF4/FGF3, PAKI, and FGR. Three genes were examined at the messenger RNA level. AR and PIK3CA were higher in normal specimens, and MET was higher in malignant samples, suggesting a role for MET in endometrial cancer. Newer arrays examining more genes and larger sample numbers are necessary to elucidate the carcinogenic pathway in endometrial cancer.

Zhang G, Cao Y, Xu Y, See WA
Micro-array analysis of the effect of post-transurethral bladder tumor resection urine on transforming growth factor-beta1 dependent gene expression in transitional cell carcinoma.
Urol Oncol. 2005 Nov-Dec; 23(6):413-8 [PubMed] Related Publications
INTRODUCTION AND OBJECTIVES: Prior studies have shown that bladder trauma occurring during transurethral bladder tumor resection increases urinary levels of the cytokine transforming growth factor (TGF)-beta1. This study used complementary deoxyribonucleic acid micro-array technology to identify additional genes in human transitional cell carcinoma (TCC), whose expression is altered as a consequence of increased urinary levels of TGF-beta1.
METHODS: The human TCC line 253J was cultured in standard media, or media spiked with either 10% post-transurethral bladder tumor resection urine (PTU), or PTU and anti-TGF-beta1 neutralizing antibody. Messenger ribonucleic acid from these conditions, together with messenger ribonucleic acid from stably transfected 253J cells over-expressing TGF-beta1, was hybridized with ATLAS micro-array membranes (Clontech, Palo Alto, CA) containing 588 human genes. Hybridization signal intensity was quantified using phospho-imaging. An analytic strategy based on the variance in the signal intensity ratio of specific housekeeping genes in control and experimental comparisons was used to identify significant changes in gene expression. Reverse transcriptase polymerase chain reaction of target genes was used to confirm gene over-expression and TGF-beta1 responsiveness.
RESULTS: Seven genes were identified on micro-array: v-RAF-1, colony stimulating factor-1 receptor, v-FGR, insulin growth factor-1 receptor, epidermal growth factor receptor, alpha5 integrin, and interferon receptor-1. Reverse transcriptase polymerase chain reaction confirmed over-expression in the autocrine TGF-beta1 producing cell line and increased expression in response to exogenous TGF-beta1.
CONCLUSIONS: TGF-beta1 in PTU alters the expression of multiple genes in human TCC in vitro. The impact of these changes on the biologic phenotype of the malignant cell and the efficacy of adjuvant therapies requires further evaluation.

Matthews J, Wihlén B, Thomsen J, Gustafsson JA
Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor alpha to 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive promoters.
Mol Cell Biol. 2005; 25(13):5317-28 [PubMed] Free Access to Full Article Related Publications
Using chromatin immunoprecipitation assays, we studied the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated recruitment of the aryl hydrocarbon receptor (AhR) and several co-regulators to the CYP1A1 promoter. AhR displayed a time-dependent recruitment, reaching a peak at 75 min and maintaining promoter occupancy for the remainder of the time course. Recruitment of AhR was followed by TIF2/SRC2, which preceded CBP, histone H3 acetylation, and RNA polymerase II (RNAPII). Simultaneous recruitment to the enhancer and the TATA box region suggests the formation of a large multiprotein complex bridging the two promoter regions. Interestingly, estrogen receptor alpha (ERalpha) displayed a TCDD- and time-dependent recruitment to the CYP1A1 promoter, which was increased by co-treatment with estradiol. Transfection in HuH7 human liver cells confirmed previously reported ERalpha enhancement of AhR activity. In contrast, TCDD did not induce the recruitment of ERalpha to the estrogen-responsive pS2 promoter, and after 120 min of co-treatment with estradiol, ERalpha is still present on the CYP1A1 promoter but no longer at pS2. RNA interference studies with T47D cells support a role for ERalpha in TCDD-dependent CYP1A1 expression. Our data suggest that ERalpha acts as a coregulator of AhR-mediated transcriptional activation and that the recruitment of ERalpha by AhR represents a novel mechanism AhR-ERalpha cross talk.

Nakahara Y, Shiraishi T, Okamoto H, et al.
Detrended fluctuation analysis of genome-wide copy number profiles of glioblastomas using array-based comparative genomic hybridization.
Neuro Oncol. 2004; 6(4):281-9 [PubMed] Free Access to Full Article Related Publications
We examined whole genomic aberrations of biopsied samples from 19 independent glioblastomas by array-based comparative genomic hybridization analysis. The highest frequencies of copy number gains were observed on RFC2 (73.3%), EGFR (63.2%), and FGR, ELN, CDKN1C , FES, TOP2A, and ARSA (57.9% each). The highest frequencies of copy number losses were detected on TBR1 (52.6%), BMI1 (52.6%), EGR2 (47.4%), DMBT1 (47.4%), MTAP (42.1%), and FGFR2 (42.1%). The copy number gains of CDKN1C and INS and the copy number losses of TBR1 were significantly correlated with longer survival of patients. High-level amplifications were identified on EGFR, SAS/CDK4, PDGFRA, MDM2, and ARSA. These genes are assumed to be involved in tumorigenesis or progression of glioblastomas. The first attempts to apply detrended fluctuation analysis to copy number profiles by considering the reading direction as the time axis demonstrated that higher long-term fractal scaling exponents (alpha2) correlated well with longer survival of glioblastoma patients. The present study indicates that array-based comparative genomic hybridization analysis has great potential for assessment of copy number changes and altered chromosomal regions of brain tumors. Furthermore, we show that nonlinear analysis methods of whole genome copy number profiles may provide prognostic information about glioblastoma patients.

Hashimoto K, Mori N, Tamesa T, et al.
Analysis of DNA copy number aberrations in hepatitis C virus-associated hepatocellular carcinomas by conventional CGH and array CGH.
Mod Pathol. 2004; 17(6):617-22 [PubMed] Related Publications
To clarify the genetic aberrations involved in the development and progression of hepatitis C virus-associated hepatocellular carcinoma (HCV-HCC), we investigated DNA copy number aberrations (DCNAs) in 19 surgically resected HCCs by conventional CGH and array CGH. Conventional CGH revealed that increases of DNA copy number were frequent at 1q (79% of the cases), 8q (37%), 6p (32%), and 10p (32%) and that decreases were frequent at 17p (79%), 16q (58%), 4q (53%), 13q (42%), 10q (37%), 1p (32%), and 8p (32%). In general, genes that showed DCNAs by array CGH were usually located in chromosomal regions with DCNAs detected by conventional CGH analysis. Increases in copy numbers of the LAMC2, TGFB2, and AKT3 genes (located on 1q) and decreases in copy numbers of FGR/SRC2 and CYLD (located on 1p and 16q, respectively) were observed in more than 30% of tumors, including small, well-differentiated carcinomas. These findings suggest that these genes are associated with the development of HCV-HCC. Increases of MOS, MYC, EXT1, and PTK2 (located on 8q) were detected exclusively in moderately and poorly differentiated tumors, suggesting that these alterations contribute to tumor progression. In conclusion, chromosomal and array CGH technologies allow identification of genes involved in the development and progression of HCV-HCC.

Hirai Y, Kawamata Y, Takeshima N, et al.
Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix.
Int J Oncol. 2004; 24(4):977-86 [PubMed] Related Publications
We established 2 novel human cell lines (GCCOT-1, GCCRK) from glassy cell carcinoma. Both cell lines showed dual tendencies of glandular and squamous differentiation, and thus possess the characteristics resembling reserve cells, the putative origin of most carcinomas arising from the uterine cervix. HPV type 18 DNA including E6-E7, which is commonly found in cell types other than squamous cell carcinoma of uterine cervix, was detected in both cell lines. We analyzed gene copy number alterations of the 2 cell lines using conventional comparative genomic hybridization (CGH) coupled with array-based CGH. Among the putative oncogenes demonstrating copy number gain in both cell lines, FGR(SRC2) at 1p36.2-1 and LAMC2 at 1q25-31 have not been reported to show amplification in previous analyses of conventional cervical cell lines. These oncogenes are thus speculated to be directly associated with oncogenesis of glassy cell carcinoma. On the other hand, among the putative suppressor genes demonstrating copy number loss in both cell lines, the 9q region, ATM at 11q22.3, and CYLD at 16q12-13 have not been reported to show loss in conventional cervical cancer cell lines. These sites are speculated to be important as tumor suppressors directly associated with oncogenesis of glassy cell carcinoma. This study suggests for the first time that together with the presence of HPV type 18, alterations at the above sites are closely associated with oncogenesis of glassy cell carcinoma, a special type of carcinoma in the uterine cervix.

Edwards J, Krishna NS, Witton CJ, Bartlett JM
Gene amplifications associated with the development of hormone-resistant prostate cancer.
Clin Cancer Res. 2003; 9(14):5271-81 [PubMed] Related Publications
PURPOSE: Hormone resistance remains a significant clinical problem in prostate cancer with few therapeutic options. Research into mechanisms of hormone resistance is essential.
EXPERIMENTAL DESIGN: We analyzed 38 paired (prehormone/posthormone resistance) prostate cancer samples using the Vysis GenoSensor. Archival microdissected tumor DNA was extracted, amplified, labeled, and hybridized to Amplionc I DNA microarrays containing 57 oncogenes.
RESULTS: Genetic instability increased during progression from hormone-sensitive to hormone-resistant cancer (P = 0.008). Amplification frequencies of 15 genes (TERC, MYBL3, HRAS, PI3KCA, JUNB, LAMC2, RAF1, MYC, GARP, SAS, FGFR1, PGY1, MYCL1, MYB, FGR) increased by >10% during hormone escape. Receptor tyrosine kinases were amplified in 73% of cases; this was unrelated to development of hormone resistance. However, downstream receptor tyrosine kinase signaling pathways showed increased amplification rates in resistant tumors for the mitogen-activated protein kinase (FGR/Src-2, HRAS, and RAF1; P = 0.005) and phosphatidylinositol 3'-kinase pathways (FGR/Src-2, PI3K, and Akt; P = 0.046). Transcription factors regulated by these pathways were also more frequently amplified after escape (MYC family: 21% before versus 63% after, P = 0.027; MYB family: 26% before versus 53% after, P = 0.18).
CONCLUSIONS: Development of clinical hormone escape is linked to phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways. These pathways may function independently of the androgen receptor or via androgen receptor activation by phosphorylation, providing novel therapeutic targets.

Hattinger CM, Reverter-Branchat G, Remondini D, et al.
Genomic imbalances associated with methotrexate resistance in human osteosarcoma cell lines detected by comparative genomic hybridization-based techniques.
Eur J Cell Biol. 2003; 82(9):483-93 [PubMed] Related Publications
Methotrexate (MTX) is one of the most important drugs for osteosarcoma (OS) treatment. To identify genetic aberrations associated with the development of MTX resistance in OS cells, in addition to the previously reported expression changes of dihydrofolate reductase (DHFR) and reduced folate carrier (RFC) genes, comparative genomic hybridization (CGH)-based techniques were used. The direct comparison between MTX-resistant variants of U-2OS or Saos-2 human OS cell lines with their respective parental cell lines by CGH on chromosomes revealed that development of MTX resistance was associated with gain of the chromosomal regions 5q12-q15 and 11q14-qter in U-2OS variants, and with gain of 8q22-qter in Saos-2 variants. Further analyses by CGH on microarrays demonstrated a progressively increasing gain of mixed lineage leukemia (MLL) gene (11q23) in U-2OS MTX-resistant variants, which was also confirmed by fluorescence in situ hybridization (FISH), in addition to gain of FGR (1p36), amplification/overexpression of DHFR, and slight decrease of RFC expression. In Saos-2 MTX-resistant variants, gain of MYC (8q24.12-q24.13) was detected, together with a remarkable decrease of RFC expression. Further analyses of DHFR, MLL, MYC, and RFC gene status in four additional human OS cell lines revealed that only gain of DHFR and MLL were associated with an inherent lower sensitivity to MTX. These data demonstrate that genetic analyses with complementary techniques are helpful for the identification of new candidate genes, which might be considered for an early identification of MTX unresponsive tumors.

Maesako Y, Uchiyama T, Ohno H
Comparison of gene expression profiles of lymphoma cell lines from transformed follicular lymphoma, Burkitt's lymphoma and de novo diffuse large B-cell lymphoma.
Cancer Sci. 2003; 94(9):774-81 [PubMed] Related Publications
To determine the specific gene expression in B-cell lymphoma subtypes, we compared expression profiles of cell lines from transformed follicular lymphoma (tFL), Epstein-Barr virus-negative (EBV(-)) Burkitt's lymphoma (BL) and EBV(+)BL. Complementary DNAs were synthesized from these cell lines and hybridized with the Atlas Human 1.2 Array membrane. Hierarchical clustering analysis based upon the levels of 43 genes highlighted characteristic expression patterns of the 3 lymphoma subtypes. Genes expressed at higher levels in tFL than EBV(-)BL and EBV(+)BL included calcium/calmodulin-dependent protein kinase I (CAMK1) and mitogen-activated protein kinase 10 (MAPK10). EBV(-)BL was characterized by high-level expression of amyloid beta precursor protein (APP), heat shock 27 kD protein 1 (HSPB1) and mothers against decapentaplegic homolog 1 (MADH1). Gardner-Rasheed feline sarcoma viral oncogene homolog (FGR) was the most significant gene to delineate EBV(+)BL. A subtype prediction algorithm using 34 genes correctly classified 22 (92%) of 24 lymphomas into FL/tFL, EBV(-)BL or EBV(+)BL. By comparison with normal reference B-cell materials, the expression patterns of the selected genes were characteristic of lymphomas. We extended the clustering analysis to cell lines from de novo diffuse large B-cell lymphoma (DLBCL). The DLBCL cell lines were either separated from the former 3 lymphoma subtypes or segregated with EBV(+)BL, possibly reflecting variable genetic abnormalities. The associations of CAMK1 with tFL, APP and MADH1 with EBV(-)BL, FGR with EBV(+)BL, and BCL2 with tFL and DLBCL were confirmed by real-time quantitative reverse transcriptase-mediated polymerase chain reaction assays. This study has provided new molecular markers, expressions of which are closely associated with B-cell lymphoma subtypes.

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