Gene Summary

Gene:TPM4; tropomyosin 4
Aliases: HEL-S-108
Summary:This gene encodes a member of the tropomyosin family of actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosins are dimers of coiled-coil proteins that polymerize end-to-end along the major groove in most actin filaments. They provide stability to the filaments and regulate access of other actin-binding proteins. In muscle cells, they regulate muscle contraction by controlling the binding of myosin heads to the actin filament. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tropomyosin alpha-4 chain
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
Show (14)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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.

  • Neoplasm Invasiveness
  • Oncogene Fusion Proteins
  • Transcriptome
  • Gene Expression
  • tau Proteins
  • Serine Endopeptidases
  • Actin Cytoskeleton
  • TPM4
  • Tumor Suppressor Proteins
  • Reproducibility of Results
  • Young Adult
  • Cell Movement
  • Molecular Sequence Data
  • Diffuse Large B-Cell Lymphoma
  • Haematological Malignancies
  • Gene Expression Profiling
  • Lung Cancer
  • Tamoxifen
  • Adolescents
  • Cancer Gene Expression Regulation
  • Base Sequence
  • DNA Sequence Analysis
  • Vimentin
  • Esophageal Cancer
  • Protein-Serine-Threonine Kinases
  • Oligonucleotide Array Sequence Analysis
  • Receptor Protein-Tyrosine Kinases
  • Childhood Cancer
  • Protein-Tyrosine Kinases
  • Chromosome 19
  • Cell Proliferation
  • Drug Resistance
  • Infant
  • Amino Acid Sequence
  • Pyridines
  • RT-PCR
  • Disease-Free Survival
  • Squamous Cell Carcinoma
  • Breast Cancer
  • Tropomyosin
  • Translocation
  • Immunophenotyping
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: TPM4 (cancer-related)

Campa MJ, Moody MA, Zhang R, et al.
Interrogation of individual intratumoral B lymphocytes from lung cancer patients for molecular target discovery.
Cancer Immunol Immunother. 2016; 65(2):171-80 [PubMed] Related Publications
Intratumoral B lymphocytes are an integral part of the lung tumor microenvironment. Interrogation of the antibodies they express may improve our understanding of the host response to cancer and could be useful in elucidating novel molecular targets. We used two strategies to explore the repertoire of intratumoral B cell antibodies. First, we cloned VH and VL genes from single intratumoral B lymphocytes isolated from one lung tumor, expressed the genes as recombinant mAbs, and used the mAbs to identify the cognate tumor antigens. The Igs derived from intratumoral B cells demonstrated class switching, with a mean VH mutation frequency of 4%. Although there was no evidence for clonal expansion, these data are consistent with antigen-driven somatic hypermutation. Individual recombinant antibodies were polyreactive, although one clone demonstrated preferential immunoreactivity with tropomyosin 4 (TPM4). We found that higher levels of TPM4 antibodies were more common in cancer patients, but measurement of TPM4 antibody levels was not a sensitive test for detecting cancer. Second, in an effort to focus our recombinant antibody expression efforts on those B cells that displayed evidence of clonal expansion driven by antigen stimulation, we performed deep sequencing of the Ig genes of B cells collected from seven different tumors. Deep sequencing demonstrated somatic hypermutation but no dominant clones. These strategies may be useful for the study of B cell antibody expression, although identification of a dominant clone and unique therapeutic targets may require extensive investigation.

Ra SH, Su A, Li X, et al.
Keratoacanthoma and squamous cell carcinoma are distinct from a molecular perspective.
Mod Pathol. 2015; 28(6):799-806 [PubMed] Related Publications
Keratoacanthoma is a controversial entity. Some consider keratoacanthoma as a variant of squamous cell carcinoma, whereas others see it as a distinct self-resolving squamoproliferative lesion. Our objective is to examine the relationship of keratoacanthoma with squamous cell carcinoma and normal skin by using DNA microarrays. DNA microarray studies were performed on formalin-fixed and paraffin-embedded blocks from ten cases of actinic keratoacanthoma utilizing the U133plus2.0 array. These results were compared with our previously developed microarray database of ten squamous cell carcinoma and ten normal skin samples. Keratoacanthoma demonstrated 1449 differentially expressed genes in comparison with squamous cell carcinoma (>5-fold change: P<0.01) with 908 genes upregulated and 541 genes downregulated. Keratoacanthoma showed 2435 differentially expressed genes in comparison with normal skin (>5-fold change: P<0.01) with 1085 genes upregulated and 1350 genes downregulated. The most upregulated genes, comparing keratoacanthoma with normal skin included MALAT1, S100A8, CDR1, TPM4, and CALM1. The most downregulated genes included SCGB2A2, DCD, THRSP, ADIPOQ, adiponectin, and ADH1B. The molecular biological pathway analysis comparing keratoacanthoma with normal skin showed that cellular development, cellular growth and proliferation, cell death/apoptosis, and cell cycle pathways are prominently involved in the pathogenesis of keratoacanthoma. The most enriched canonical pathways were clathrin-mediated endocytosis signaling, molecular mechanisms of cancer and integrin signaling. The distinctive gene expression profile of keratoacanthoma reveals that it is molecularly distinct from squamous cell carcinoma. The molecular pathways and genes differentially expressed in comparing keratoacanthoma with normal skin suggest that keratoacanthoma is a neoplasm that can regress due to upregulation of the cell death/apoptosis pathway.

Wang J, Guan J, Lu Z, et al.
Clinical and tumor significance of tropomyosin-1 expression levels in renal cell carcinoma.
Oncol Rep. 2015; 33(3):1326-34 [PubMed] Related Publications
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and has been described as one of the deadliest of cancers affecting the genitourinary tract. Tropomyosin is a two-stranded α-helical coiled coil protein found in cell cytoskeletons. One of its isoforms, tropomyosin-1 (TPM1) has been reported as a novel tumor-suppressor gene and is downregulated in many solid tumors. However the expression level and function of TPM1 in RCC have not yet been determined. In the present study, we evaluated the TPM1-4 mRNA and TPM1 protein levels in RCC tissue samples. TPM1-overexpressing OSRC-2 and 786-O cell lines were also used to investigate the impact of TPM1 on RCC cells. We found that TPM1 was significantly and specifically downregulated in the RCC tissues. TPM1 expression was associated with tumor size, smoking status, Fuhrman grade and the prognosis of RCC patients. After TPM1 transfection, the migratory and invasive abilities of the OSRC-2 and 786-O cell lines were both reduced when compared to the control groups. Meanwhile, apoptosis was also enhanced in these two RCC cell lines following TPM1 transfection. Taken together, TPM1 exhibits characteristics of a tumor-suppressor gene while being overexpressed in RCC cell lines.

Singleton DC, Rouhi P, Zois CE, et al.
Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis.
Oncogene. 2015; 34(36):4713-22 [PubMed] Free Access to Full Article Related Publications
Hypoxia is a common feature of locally advanced breast cancers that is associated with increased metastasis and poorer survival. Stabilisation of hypoxia-inducible factor-1α (HIF1α) in tumours causes transcriptional changes in numerous genes that function at distinct stages of the metastatic cascade. We demonstrate that expression of RIOK3 (RIght Open reading frame kinase 3) was increased during hypoxic exposure in an HIF1α-dependent manner. RIOK3 was localised to distinct cytoplasmic aggregates in normoxic cells and underwent redistribution to the leading edge of the cell in hypoxia with a corresponding change in the organisation of the actin cytoskeleton. Depletion of RIOK3 expression caused MDA-MB-231 to become elongated and this morphological change was due to a loss of protraction at the trailing edge of the cell. This phenotypic change resulted in reduced cell migration in two-dimensional cultures and inhibition of cell invasion through three-dimensional extracellular matrix. Proteomic analysis identified interactions of RIOK3 with actin and several actin-binding factors including tropomyosins (TPM3 and TPM4) and tropomodulin 3. Depletion of RIOK3 in cells resulted in fewer and less organised actin filaments. Analysis of these filaments showed reduced association of TPM3, particularly during hypoxia, suggesting that RIOK3 regulates actin filament specialisation. RIOK3 depletion reduced the dissemination of MDA-MB-231 cells in both a zebrafish model of systemic metastasis and a mouse model of pulmonary metastasis. These findings demonstrate that RIOK3 is necessary for maintaining actin cytoskeletal organisation required for migration and invasion, biological processes that are necessary for hypoxia-driven metastasis.

Vasiljević N, Ahmad AS, Carter PD, et al.
DNA methylation of PITX2 predicts poor survival in men with prostate cancer.
Biomark Med. 2014; 8(9):1143-50 [PubMed] Related Publications
AIM: We investigated if methylation of candidate genes can be useful for predicting prostate cancer (PCa) specific death.
PATIENTS & METHODS: Methylation of PITX2, WNT5a, SPARC, EPB41L3 and TPM4 was investigated in a 1:2 case-control cohort comprising 45 men with cancer of Gleason score ≤ 7 who died (cases), and 90 men who were alive or died of other causes with survival time longer than the cases (controls). A univariate conditional logistic regression model was fitted by maximizing the likelihood of DNA methylation of each gene versus the primary end point.
RESULTS: A 10% increase in methylation of PITX2 was associated with PCa related death with OR 1.56 (95% CI: 1.17-2.08; p = 0.005).
CONCLUSION: Our study strengthens prior findings that PITX2 methylation is useful as a biomarker of poor outcome of PCa and in addition we also suggest that it may be particularly useful in men with low Gleason score.

Yang J, Annala M, Ji P, et al.
Recurrent LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes promote tumor cell motility in human osteosarcoma.
J Hematol Oncol. 2014; 7:76 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The identification of fusion genes such as SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK and EWS-FLI1 in human sarcomas has provided important insight into the diagnosis and targeted therapy of sarcomas. No recurrent fusion has been reported in human osteosarcoma.
METHODS: Transcriptome sequencing was used to characterize the gene fusions and mutations in 11 human osteosarcomas.
RESULTS: Nine of 11 samples were found to harbor genetic inactivating alterations in the TP53 pathway. Two recurrent fusion genes associated with the 12q locus, LRP1-SNRNP25 and KCNMB4-CCND3, were identified and validated by RT-PCR, Sanger sequencing and fluorescence in situ hybridization, and were found to be osteosarcoma specific in a validation cohort of 240 other sarcomas. Expression of LRP1-SNRNP25 fusion gene promoted SAOS-2 osteosarcoma cell migration and invasion. Expression of KCNMB4-CCND3 fusion gene promoted SAOS-2 cell migration.
CONCLUSIONS: Our study represents the first whole transcriptome analysis of untreated human osteosarcoma. Our discovery of two osteosarcoma specific fusion genes associated with osteosarcoma cellular motility highlights the heterogeneity of osteosarcoma and provides opportunities for new treatment modalities.

Häbig K, Gellhaar S, Heim B, et al.
LRRK2 guides the actin cytoskeleton at growth cones together with ARHGEF7 and Tropomyosin 4.
Biochim Biophys Acta. 2013; 1832(12):2352-67 [PubMed] Related Publications
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common genetic cause of Parkinson's disease (PD). However, LRRK2 function and molecular mechanisms causing the parkinsonian phenotype remain widely unknown. Most of LRRK2 knockdown and overexpression models strengthen the relevance of LRRK2 in regulating neurite outgrowth. We have recently identified ARHGEF7 as the first guanine nucleotide exchange factor (GEF) of LRRK2. This GEF is influencing neurite outgrowth through regulation of actin polymerization. Here, we examined the expression profile of neuroblastoma cells with reduced LRRK2 and ARHGEF7 levels to identify additional partners of LRRK2 in this process. Tropomyosins (TPMs), and in particular TPM4, were the most interesting candidates next to other actin cytoskeleton regulating transcripts in this dataset. Subsequently, enhanced neurite branching was shown using primary hippocampal neurons of LRRK2 knockdown animals. Furthermore, we observed an enhanced number of growth cones per neuron and a mislocalization and dysregulation of ARHGEF7 and TPM4 in these neuronal compartments. Our results reveal a fascinating connection between the neurite outgrowth phenotype of LRRK2 models and the regulation of actin polymerization directing further investigations of LRRK2-related pathogenesis.

Mihály Z, Kormos M, Lánczky A, et al.
A meta-analysis of gene expression-based biomarkers predicting outcome after tamoxifen treatment in breast cancer.
Breast Cancer Res Treat. 2013; 140(2):219-32 [PubMed] Related Publications
To date, three molecular markers (ER, PR, and CYP2D6) have been used in clinical setting to predict the benefit of the anti-estrogen tamoxifen therapy. Our aim was to validate new biomarker candidates predicting response to tamoxifen treatment in breast cancer by evaluating these in a meta-analysis of available transcriptomic datasets with known treatment and follow-up. Biomarker candidates were identified in Pubmed and in the 2007-2012 ASCO and 2011-2012 SABCS abstracts. Breast cancer microarray datasets of endocrine therapy-treated patients were downloaded from GEO and EGA and RNAseq datasets from TCGA. Of the biomarker candidates, only those identified or already validated in a clinical cohort were included. Relapse-free survival (RFS) up to 5 years was used as endpoint in a ROC analysis in the GEO and RNAseq datasets. In the EGA dataset, Kaplan-Meier analysis was performed for overall survival. Statistical significance was set at p < 0.005. The transcriptomic datasets included 665 GEO-based and 1,208 EGA-based patient samples. All together 68 biomarker candidates were identified. Of these, the best performing genes were PGR (AUC = 0.64, p = 2.3E-07), MAPT (AUC = 0.62, p = 7.8E-05), and SLC7A5 (AUC = 0.62, p = 9.2E-05). Further genes significantly correlated to RFS include FOS, TP53, BTG2, HOXB7, DRG1, CXCL10, and TPM4. In the RNAseq dataset, only ERBB2, EDF1, and MAPK1 reached statistical significance. We evaluated tamoxifen-resistance genes in three independent platforms and identified PGR, MAPT, and SLC7A5 as the most promising prognostic biomarkers in tamoxifen treated patients.

Tang HY, Beer LA, Tanyi JL, et al.
Protein isoform-specific validation defines multiple chloride intracellular channel and tropomyosin isoforms as serological biomarkers of ovarian cancer.
J Proteomics. 2013; 89:165-78 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: New serological biomarkers for early detection and clinical management of ovarian cancer are urgently needed, and many candidates have been reported. A major challenge frequently encountered when validating candidates in patients is establishing quantitative assays that distinguish between highly homologous proteins. The current study tested whether multiple members of two recently discovered ovarian cancer biomarker protein families, chloride intracellular channel (CLIC) proteins and tropomyosins (TPM), were detectable in ovarian cancer patient sera. A multiplexed, label-free multiple reaction monitoring (MRM) assay was established to target peptides specific to all detected CLIC and TPM family members, and their serum levels were quantitated for ovarian cancer patients and non-cancer controls. In addition to CLIC1 and TPM1, which were the proteins initially discovered in a xenograft mouse model, CLIC4, TPM2, TPM3, and TPM4 were present in ovarian cancer patient sera at significantly elevated levels compared with controls. Some of the additional biomarkers identified in this homolog-centric verification and validation approach may be superior to the previously identified biomarkers at discriminating between ovarian cancer and non-cancer patients. This demonstrates the importance of considering all potential protein homologs and using quantitative assays for cancer biomarker validation with well-defined isoform specificity.
BIOLOGICAL SIGNIFICANCE: This manuscript addresses the importance of distinguishing between protein homologs and isoforms when identifying and validating cancer biomarkers in plasma or serum. Specifically, it describes the use of targeted in-depth LC-MS/MS analysis to determine the members of two protein families, chloride intracellular channel (CLIC) and tropomyosin (TPM) proteins that are detectable in sera of ovarian cancer patients. It then establishes a multiplexed isoform- and homology-specific MRM assay to quantify all observed gene products in these two protein families as well as many of the closely related tropomyosin isoforms. Using this assay, levels of all detected CLICs and TPMs were quantified in ovarian cancer patient and control subject sera. These results demonstrate that in addition to the previously known CLIC1, multiple tropomyosins and CLIC4 are promising new ovarian cancer biomarkers. Based on these initial validation studies, these new ovarian cancer biomarkers appear to be superior to most previously known ovarian cancer biomarkers.

Mendes-Pereira AM, Sims D, Dexter T, et al.
Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen.
Proc Natl Acad Sci U S A. 2012; 109(8):2730-5 [PubMed] Free Access to Full Article Related Publications
Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRC5D, NAE1, NF1, NIPBL, NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silencing causes sensitivity to this endocrine agent (C10orf72, C15orf55/NUT, EDF1, ING5, KRAS, NOC3L, PPP1R15B, RRAS2, TMPRSS2, and TPM4). Multiple individual genes, including NF1, a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment.

Kopantzev EP, Monastyrskaya GS, Vinogradova TV, et al.
Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma.
Lung Cancer. 2008; 62(1):23-34 [PubMed] Related Publications
We, for the first time, directly compared gene expression profiles in human non-small cell lung carcinomas (NSCLCs) and in human fetal lung development. Previously reported correlations of gene expression profiles between lung cancer and lung development, deduced from matching data on mouse development and human cancer, have brought important information, but suffered from different timing of mouse and human gene expression during fetal development and fundamental differences in tumorigenesis in mice and humans. We used the suppression subtractive hybridization technique to subtract cDNAs prepared from human fetal lung samples at weeks 10-12 and 22-24 and obtained a cDNA library enriched in the transcripts more abundant at the later stage. cDNAs sequencing and RT-PCR analysis of RNAs from human fetal and adult lungs revealed 12 differentially transcribed genes: ADH1B, AQP1, FOLR1, SLC34A2, CAV1, INMT, TXNIP, TPM4, ICAM-1, HLA-DRA, EFNA1 and HLA-E. Most of these genes were found up-regulated in mice and rats at later stages than in human lung development. In surgical samples of NSCLC, these genes were down-regulated as compared to surrounding normal tissues and normal lungs, thus demonstrating opposite expression profiles for the genes up-regulated during fetal lung development.

Jazii FR, Najafi Z, Malekzadeh R, et al.
Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer.
World J Gastroenterol. 2006; 12(44):7104-12 [PubMed] Free Access to Full Article Related Publications
AIM: To assess the proteome of normal versus tumor tissue in squamous cell carcinoma of the esophagus (SCCE) in Iranian patients and compare our results with former reports by using proteomics.
METHODS: Protein was extracted from normal and tumor tissues. Two dimensional electrophoresis was carried out and spots with differential expression were identified with mass spectrometry. RNA extraction and RT-PCR along with immunodetection were performed.
RESULTS: Fourteen proteins were found whose expression levels differed in tumor compared to normal tissues. Mass spectrometric analysis resulted in the identification of beta-tropomyosin (TMbeta), myosin light chain 2 (and its isoform), myosin regulatory light chain 2, peroxyredoxin 2, annexin I and an unknown polypeptide as the down regulated polypeptides in tumor tissue. Heat shock protein 70 (HSP70), TPM4-ALK fusion oncoprotein 2, myosin light polypeptide 6, keratin I, GH16431p and calreticulin were the up-regulated polypeptides found in tumor tissue. Several of these proteins, such as TMbeta, HSP70, annexin I, calreticulin, TPM4-ALK and isoforms of myosins, have been well recognized in tumorigenesis of esophageal or other types of cancers.
CONCLUSION: Our study not only supports the involvement of some of the formerly reported proteins in SCCE but also introduces additional proteins found to be lost in SCCE, including TMbeta.

Yamamoto H, Kohashi K, Oda Y, et al.
Absence of human herpesvirus-8 and Epstein-Barr virus in inflammatory myofibroblastic tumor with anaplastic large cell lymphoma kinase fusion gene.
Pathol Int. 2006; 56(10):584-90 [PubMed] Related Publications
Inflammatory myofibroblastic tumor (IMT) is clinically and histologically characterized by inflammation. Some populations of IMT have anaplastic large cell lymphoma kinase (ALK) gene rearrangements. Infection with Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) in tumor cells of IMT has been reported; these reports, however, have been limited to ALK-negative IMT. The purpose of the present paper was to evaluate 21 cases of IMT for the presence of EBV and HHV-8. Immunohistochemically, 15 cases were ALK positive and six were negative. Of eight cases analyzed using reverse transcription-polymerase chain reaction, tropomyosin 3 (TPM3)-ALK, TPM4-ALK and clathrin heavy chain-ALK fusion genes were detected in one, two and two cases, respectively. All 21 IMT, irrespective of ALK expression, were negative for EBV by in situ hybridization for EBV-encoded RNA and immunohistochemical stain for latent membrane antigen-1. HHV-8 was also negative in all IMT by PCR for HHV-8 DNA sequence (KS330/233) and immunohistochemical stain for latent nuclear antigen. These results suggest that IMT may be a heterogeneous group in terms of pathogenesis, and EBV and HHV-8 do not play a major role in the pathogenesis of ALK-positive tumor.

Qi Y, Chiu JF, Wang L, et al.
Comparative proteomic analysis of esophageal squamous cell carcinoma.
Proteomics. 2005; 5(11):2960-71 [PubMed] Related Publications
Ranking as the fourth commonest cancer, esophageal squamous cell carcinoma (ESCC) represents one of the leading causes of cancer death in China. One of the main reasons for the low survival rate is that neoplasms in esophagus are not detected until they have invaded into surrounding tissues or spread throughout the body at advanced stages. A better understanding of the malignant mechanism and early diagnosis are important for fighting ESCC. In this study, we used proteomics to analyze ESCC tissues, aiming at defining the proteomic features implicated in the multistage progression of esophageal carcinogenesis. Proteins that exhibited significantly different expressions were identified by peptide mass fingerprinting and validated by Western blotting and reverse transcriptase-polymerase chain reaction. The protein changes were then correlated to the different grades of disease differentiation. Compared to those in adjacent normal epitheliums, the expression of 15 proteins including enolase, elongation factor Tu, isocitrate dehydrogenase, tubulin alpha-1 chain, tubulin beta-5 chain, actin (cytoplasmic 1), glyceraldehyde-3 phosphate dehydrogenase, tropomyosin isoform 4 (TPM4), prohibitin, peroxiredoxin 1 (PRX1), manganese-containing superoxide dismutase (MnSOD), neuronal protein, and transgelin was up-regulated; and the expression of five proteins including TPM1, squamous cell carcinoma antigen 1 (SCCA1), stratifin, peroxiredoxin 2 isoform a, and alpha B crystalline was down-regulated in cancer tissues with a statistical significance (p < 0.05). In addition, the differential expression of SCCA1, PRX1, MnSOD, TPM4, and prohibitin can be observed in precancerous lesions of ESCC. The expression of stratifin, prohibitin, and SCCA1 dropped with increasing dedifferentiation of ESCC. These data may suggest that these proteins contribute to the multistage process of carcinogenesis, tumor progression, and invasiveness of ESCC.

Fisher C
Low-grade sarcomas with CD34-positive fibroblasts and low-grade myofibroblastic sarcomas.
Ultrastruct Pathol. 2004 Sep-Dec; 28(5-6):291-305 [PubMed] Related Publications
A subset of low-grade fibrosarcomas is composed of CD34-positive spindle cells. These include dermatofibrosarcoma, its morphologic variants, and its associated fibrosarcoma, solitary fibrous tumor, hemangiopericytoma and their malignant counterparts, and some cases of myxoinflammatory fibroblastic sarcoma. Dermatofibrosarcoma and related lesions are characterized by a t(17;22)(q22;q13) rearrangement resulting in fusion of the genes COL1A (17q21-22) and PDGFB1 (22q13). Solitary fibrous tumor displays varying cellularity and fibrosis and a peripheral hemangiopericytomatous pattern; most tumors formerly called hemangiopericytoma are now subsumed into the category of solitary fibrous tumor, although a few strictly defined examples are recognized; however, these are probably not composed of pericytes. Myofibroblastic malignancies are best identified by electron microscopy, with which varying degrees of differentiation, including the presence of fibronexus junctions, can be identified. Low-grade sarcomas showing myofibroblastic differentiation include myofibrosarcomas and inflammatory myofibroblastic tumors. Myofibrosarcomas are spindle cell neoplasms that occur in children or adults in the head and neck, trunk, and extremities as infiltrative neoplasms and that display a fascicular or fasciitis-like pattern with focal nuclear atypia and variable expression of myoid antigens. These sarcomas are prone to recurrence and a small number metastasize. Inflammatory myofibroblastic tumor (synonymous with inflammatory fibrosarcoma) is a neoplasm arising predominantly in childhood, and frequently in intraabdominal locations. It has spindle cells in fascicular, fasciitis-like and sclerosing patterns, with heavy chronic inflammation including abundant plasma cells. Many IMT have clonal chromosomal abnormalities involving 2p22-24, and fusion of the ALK gene with tropomyosin 3 (TPM3-ALK) or tropomyosin 4 (TPM4-ALK) is found in a subset.

Liang X, Meech SJ, Odom LF, et al.
Assessment of t(2;5)(p23;q35) translocation and variants in pediatric ALK+ anaplastic large cell lymphoma.
Am J Clin Pathol. 2004; 121(4):496-506 [PubMed] Related Publications
To evaluate t(2;5) and its variants, we studied 21 pediatric cases of anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) by using immunohistochemical staining, fluorescence in situ hybridization, cytogenetics, and reverse transcriptase-polymerase chain reaction. Results showed 7 (33%) cases with t(2;5), 6 (29%) with variant gene rearrangements, 7 (33%) with uncharacterized rearrangements, and 1 with ALK protein expression but no ALK rearrangement. Among 6 variant gene rearrangements, 1 had TPM4-ALK/t(2;19)(p23;p13) and 2 had inv(2) with the breakpoint proximate to ATIC-ALK and an unknown partner gene separately. The genetic features of the remaining 3 cases were as follows: ins(8;2) with an unknown partner gene; conversion from ALK- at diagnosis to ALK+ at recurrence with unspecified gene rearrangement; complex karyotype without involvement of 2p23, suggesting a cryptic translocation. Concordance between different laboratory results varied from 47% to 81%. These data suggest that ALK variants are not uncommon and underscore the necessity of integrating immunohistochemical, cytogenetic, and molecular genetic approaches to detect, characterize, and confirm t(2;5) and its variant translocations.

Lamant L, Gascoyne RD, Duplantier MM, et al.
Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma.
Genes Chromosomes Cancer. 2003; 37(4):427-32 [PubMed] Related Publications
In anaplastic large cell lymphoma, the ALK gene at 2p23 is known to be fused to NPM, TPM3, TPM4, TFG, ATIC, CLTC, MSN, and ALO17. All of these translocations result in the expression of chimeric ALK transcripts that are translated into fusion proteins with tyrosine kinase activity and oncogenic properties. We report a case showing a restricted cytoplasmic staining pattern of ALK and a novel chromosomal abnormality, t(2;22)(p23;q11.2), demonstrated by fluorescence in situ hybridization analysis. The result of 5' RACE analysis showed that the ALK gene was fused in-frame to a portion of the non-muscle myosin heavy chain gene, MYH9. Nucleotide sequence of the MYH9-ALK chimeric cDNA revealed that the ALK breakpoint was different from all those previously reported. It is localized in the same exonic sequence as MSN-ALK, but 6 bp downstream, resulting in an in-frame fusion of the two partner proteins. In contrast to the previously reported ALK fusion proteins, MYH9-ALK may lack a functional oligomerization domain. However, biochemical analysis showed that the new fusion protein is tyrosine phosphorylated in vivo but seems to lack tyrosine kinase activity in vitro. If further investigations confirm this latter result, the in vivo tyrosine phosphorylation of MYH9-ALK protein could involve mechanisms different from those described in the other ALK hybrid proteins.

Meech SJ, McGavran L, Odom LF, et al.
Unusual childhood extramedullary hematologic malignancy with natural killer cell properties that contains tropomyosin 4--anaplastic lymphoma kinase gene fusion.
Blood. 2001; 98(4):1209-16 [PubMed] Related Publications
This report describes an unusual extramedullary hematologic malignancy in an 18-month-old child who presented with a capillary leak syndrome that evolved into hyperleukocytosis with malignant cells. The circulating tumor cells did not express an antigen profile typical of any subtype of leukemia commonly observed in children. Tumor cells were CD3(-)/CD56(+); had germline TCR genes; and strongly expressed CD30, epithelial membrane antigen, and anaplastic lymphoma kinase (ALK) consistent with a null cell anaplastic large cell lymphoma (ALCL). The malignant cells contained a t(2;19)(p23;p13.1) that interrupted ALK and translocated it to the der(19). Reverse transcriptase-polymerase chain reaction and nucleotide sequence analysis revealed fusion of ALK to tropomyosin 4, an ALK fusion partner not described previously in hematologic malignancies. The clinical presentation and phenotypic features of this malignancy were not typical for ALCL because tumor cells expressed both myeloid (CD13, CD33, HLA-DR) and natural killer (NK) cell antigens. The neoplastic cells most resembled NK cells because in addition to being CD3(-)/CD56(+) with germline TCR genes, these cells were CD25(+)/CD122(+)/granzyme B(+) and possessed the functional properties of immature NK cells. The unusual clinical presentation, immunophenotype, and functional properties of these neoplastic cells suggest that this malignancy may be derived from the putative myeloid-NK precursor cell. Furthermore co-expression of NK and ALCL features supports the concept that a minority of null-ALCL may be derived from NK cells and expands the spectrum of phenotypes that can be seen in tumors produced by ALK fusion proteins. (Blood. 2001;98:1209-1216)

Cheuk W, Chan JK
Timely topic: anaplastic lymphoma kinase (ALK) spreads its influence.
Pathology. 2001; 33(1):7-12 [PubMed] Related Publications
Anaplastic lymphoma kinase (ALK) is normally not expressed in human tissues except selected sites in the nervous system. Its expression and constitutive activation as a result of a chromosomal translocation involving 2p23 plays a pivotal role in the genesis of anaplastic large cell lymphoma. ALK expression has been instrumental in defining a homogeneous subset from the category of anaplastic large cell lymphoma, characterised by occurrence in young patients, primary systemic presentation, favorable prognosis, a broad morphological spectrum, nuclear and/or cytoplasmic immunostaining for ALK protein, and a number of possible fusion partner genes such as NPM, ATIC, TFG, TPM3 and CLTCL. Recently ALK has been implicated in the genesis of another tumour type, the inflammatory myofibroblastic tumours. The ALK-positive examples occur in children and young adults, involving a variety of sites, such as the abdomen, mesentery, liver, bladder, mediastinum, lung and bone. The partner genes identified in some cases are TPM3 (tropomyosin 3) and TPM4 (tropomyosin 4). These molecular findings also further support the neoplastic nature of at least a subset of inflammatory myofibroblastic tumours.

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