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VTCN1 (V-set domain containing T cell activation inhibitor 1)

Identity

Other namesB7H4
B7-H4
B7S1
B7X
B7h.5
FLJ22418
PRO1291
RP11-229A19.4
HGNC (Hugo) VTCN1
LocusID (NCBI) 79679
Location 1p13.1
Location_base_pair Starts at 117686209 and ends at 117746458 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description The VTCN1 (B7-H4) gene located in chromosome 1p13.1, consists of six exons and five introns and the coding region spans 849 bp. The mature protein is coded by the exons 3, 4, and part 5 while exons 1 and 2 encodes a signal peptide. The IgV-IgC domain, comprised of the extracellular region, is coded by exons 3, 4 and parts of 5 (Chen L. et al. 2003).
Transcription B7-H4 mRNA can be detected in many tissues including placenta, kidney, liver, lung, ovary, testis and spleen. There are two transcripts of B7-H4 and both transcripts share complete homology with exons 1 to 5 in the full length B7-H4 gene. The smaller transcript of the two, generated by alternative splicing, lacks part of exon 6 (Chen L. et al. 2003).
Pseudogene A possible B7-H4 pseudogene has a single exon with 94% similar nucleotide sequence identity to the cDNA of B-7H4 and is located in chromosome 20p11.1 (Chen L. et al. 2003).

Protein

Description The predicted 282-amino acid B7-H4 protein contains a 2-amino acid intracellular domain, a large hydrophobic type 1 transmembrane domain and an extracellular domain (Prasad et al. 2003).
Expression Prasad et al. (2003) showed that B7-H4 is expressed in professional antigen presenting cells. Although B7-H4 is overexpressed in several human cancers including ovary, endometrium, lung and kidney, its expression is limited in normal tissues. Shroyer et al. (2005) showed that there is a limited focal expression of B7-H4 by immunohistochemistry in several normal human tissues including fallopian tubes, endometrial glands, pancreas, larynx, lung, kidney and urinary bladder.
Localisation B7-H4 is localized to the cell surface and cytoplasm of epithelial cells and macrophages. Expression in benign glandular cells (ductal epithelium in breast and pancreas) is localized to the apical cell surface but there is circumferential membranous localization in B7-H4 positive tumor cells.
Function Published data shows that B7-H4 functions as a negative regulator of T cell responses and it negatively regulates the T cell immunity by the inhibition of T cell proliferation, cytokine production and cell cycle progression. Prasad et al. (2003) reported that B7S1/B7-H4 is expressed on professional antigen presenting cells, binds to its putative receptor on activated T cells, and inhibits T cell activation and IL2 production. Sica G.L..et al (2003) also reported that B7-H4 inhibits T cell activation and the production of both IL2 and IL10. They further showed that B7-H4 inhibits the induction of Cytolytic T Lymphocytes (CTL) in vitro and it also arrests cell cycle of T cells in G0/G1 phase.
B7-H4 may also play a role in tumor biology by providing tumors with a protective mechanism to escape from immune surveillance. Several human cancers such ovary, endometrium, breast, kidney and lung (non small cell) are known to overexpress B-7H4 and the level of B7-H4 expression in these tumors has been correlated to the number of tumor-associated and tumor-infiltrating T cells. Papkoff J. et al. (2005) found that overexpressed B7-H4 promotes epithelial cell transformation by protecting cells from apoptosis and a siRNA knockout of B7-H4 in tumor cell lines lead to an increased apoptosis. Kryczek et al. (2006) reported that primary ovarian tumor cells express exclusively intracellular B7-H4 protein, whereas the majority of ovarian tumor macrophages, but not tumor T cells or blood macrophages, express surface B7-H4, possibly by stimulation with tumor-associated IL6 and IL10. They also showed that B7-H4 expressing tumor macrophages suppressed HER2 specific T-cell proliferation and cytotoxicity. Further, the blocking of B7-H4 expression with specific oligonucleotides improved the tumor-associated antigen T-cell responses. They concluded that B7-H4 expressing tumor macrophages are a suppressive cell population in ovarian cancer and might prove to be a good therapeutic target.
Homology B7-H4 shares a 24%-31% homology with other members of the B7 family and has the highest homology with B7H3 with 31% homology (Chen L. et al. 2003).

Implicated in

Entity Ovarian Cancer
Note Chen L et al.(2003) first reported the detection of B7-H4 expression in ovarian cancer but not in normal ovarian tissue. Papkoff et al. (2005) showed that B7-H4 mRNA and protein are overexpressed in human serous ovarian cancers and breast cancers with relatively little or no expression in normal tissues. Also they described that overexpression of B7-H4 in a human ovarian cancer cell line with little endogenous B7-H4 expression, increased the tumor formation in SCID mice. Shroyer et al. (2006) found that B7-H4 is highly over-expressed in primary and metastatic serous, endometrioid, and clear cell carcinomas. In contrast, B7-H4 is not expressed in most mucinous ovarian cancers. Kryczek I et al (2006) published that primary ovarian tumor cells express intracellular B7-H4, whereas a fraction of tumor macrophages expressed surface B7-H4. These authors concluded that B7-H4 expression in tumor macrophages, rather than in the ovarian tumor cells, was relevant with regard to the suppression of tumor-associated antigen-specific T cell immunity. Kim NW et al (2006) showed that elevated levels of B7-H4 can be found in the serum of patients with ovarian cancer and could play a role as a biomarker in ovarian cancer. They also developed a method based on ELISA to detect B7-H4 in the serum. Diamandis E.P. (2007) reported B7-H4 expression was low in normal ovaries and in benign tumors while half of early stage and two-thirds of late stage cancers over-expressed B7-H4.
  
Entity Uterine Endometrial Cancer
Note Shroyer K. et al (2007) showed that the proportion and intensity of B7-H4 staining were increased in the progression from normal, hyperplastic and malignant endometrial glandular mucosa. The proportion of B7-H4 positive tumor cells and staining intensity was also higher in high risk tumors than in low risk tumors. The proportion of B7-H4 positive tumor cells was inversely related to the number of CD3-positive and CD8-positive tumor-associated lymphocytes.
  
Entity Breast Cancer
Note Shroyer et al. (2005) showed that B7-H4 is consistently over-expressed in primary and metastatic ductal and lobular breast cancers and its expression is correlated with a negative progesterone receptor status, negative Her-2/neu status and with a history of neo-adjuvant chemotherapy. There was also a significant association between a high proportion of B7-H4 positive cells in invasive ductal carcinomas and decreased number of tumor infiltrating lymphocytes. B7-H4 immunohistochemical expression was independent of tumor grade, stage or the size of the tumors.
  
Entity Non Small Cell Lung Cancer
Note Wang X. et al (2006) showed that B7-H4 is overexpressed in Non Small Cell Lung Cancer and its overexpression is negatively correlated with tumor infiltrating lymphocytes and positively associated with lymph node metastasis.
  
Entity Renal Cell Cancer (RCC)
Note Kwon E.D. et al (2006) reported that B7-H4 was overexpressed in 59% of 259 RCC tumor specimens analyzed and that tumor cell B7-H4 expression was associated with adverse clinical and pathologic features, including constitutional symptoms, tumor necrosis, and advanced tumor size, stage, and grade. Also B7-H4 expression when coupled with B7S1 expression was associated with a poor survival from RCC. Additionally, they noted that tumor vasculature was significantly positive for endothelial B7-H4 expression, compared with the normal adjacent renal tissue vessels.
  
Entity Prostate Cancer
Note Allison J.P. et al (2007) published that B7x/B7-H4 is overexpressed in human prostate cancer and patients with stronger immunohistochemical B7-H4 expression had higher rates of clinical cancer recurrences and cancer specific deaths.
  

External links

Nomenclature
HGNC (Hugo)VTCN1   28873
Cards
AtlasVTCN1ID44144ch1p13
Entrez_Gene (NCBI)VTCN1  79679  V-set domain containing T cell activation inhibitor 1
GeneCards (Weizmann)VTCN1
Ensembl (Hinxton)ENSG00000134258 [Gene_View]  chr1:117686209-117746458 [Contig_View]  VTCN1 [Vega]
ICGC DataPortalENSG00000134258
AceView (NCBI)VTCN1
Genatlas (Paris)VTCN1
WikiGenes79679
SOURCE (Princeton)NM_001253849 NM_001253850 NM_024626
Genomic and cartography
GoldenPath (UCSC)VTCN1  -  1p13.1   chr1:117686209-117746458 -  1p12   [Description]    (hg19-Feb_2009)
EnsemblVTCN1 - 1p12 [CytoView]
Mapping of homologs : NCBIVTCN1 [Mapview]
OMIM608162   
Gene and transcription
Genbank (Entrez)AI686571 AK026071 AK225413 AK303466 AK310812
RefSeq transcript (Entrez)NM_001253849 NM_001253850 NM_024626
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NT_032977 NW_001838594 NW_004929290
Consensus coding sequences : CCDS (NCBI)VTCN1
Cluster EST : UnigeneHs.546434 [ NCBI ]
CGAP (NCI)Hs.546434
Alternative Splicing : Fast-db (Paris)GSHG0002399
Alternative Splicing GalleryENSG00000134258
Gene ExpressionVTCN1 [ NCBI-GEO ]     VTCN1 [ SEEK ]   VTCN1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ7Z7D3 (Uniprot)
NextProtQ7Z7D3  [Medical]
With graphics : InterProQ7Z7D3
Splice isoforms : SwissVarQ7Z7D3 (Swissvar)
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)   
Domains : Interpro (EBI)Ig-like_dom    Ig-like_fold    Ig_sub    Ig_V-set   
Related proteins : CluSTrQ7Z7D3
Domain families : Pfam (Sanger)V-set (PF07686)   
Domain families : Pfam (NCBI)pfam07686   
Domain families : Smart (EMBL)IG (SM00409)  
DMDM Disease mutations79679
Blocks (Seattle)Q7Z7D3
PDB (SRS)4GOS   
PDB (PDBSum)4GOS   
PDB (IMB)4GOS   
PDB (RSDB)4GOS   
Human Protein AtlasENSG00000134258
Peptide AtlasQ7Z7D3
HPRD06429
IPIIPI00640575   IPI00644574   IPI00479574   IPI01010591   IPI00302614   
Protein Interaction databases
DIP (DOE-UCLA)Q7Z7D3
IntAct (EBI)Q7Z7D3
FunCoupENSG00000134258
BioGRIDVTCN1
IntegromeDBVTCN1
STRING (EMBL)VTCN1
Ontologies - Pathways
QuickGOQ7Z7D3
Ontology : AmiGOresponse to protozoan  immune system process  receptor binding  external side of plasma membrane  integral component of membrane  negative regulation of T cell activation  interleukin-4 secretion  interferon-gamma secretion  
Ontology : EGO-EBIresponse to protozoan  immune system process  receptor binding  external side of plasma membrane  integral component of membrane  negative regulation of T cell activation  interleukin-4 secretion  interferon-gamma secretion  
Pathways : KEGGCell adhesion molecules (CAMs)   
Protein Interaction DatabaseVTCN1
Wikipedia pathwaysVTCN1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)VTCN1
SNP (GeneSNP Utah)VTCN1
SNP : HGBaseVTCN1
Genetic variants : HAPMAPVTCN1
1000_GenomesVTCN1 
ICGC programENSG00000134258 
CONAN: Copy Number AnalysisVTCN1 
Somatic Mutations in Cancer : COSMICVTCN1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)1:117686209-117746458
Mutations and Diseases : HGMDVTCN1
OMIM608162   
MedgenVTCN1
GENETestsVTCN1
Disease Genetic AssociationVTCN1
Huge Navigator VTCN1 [HugePedia]  VTCN1 [HugeCancerGEM]
Genomic VariantsVTCN1  VTCN1 [DGVbeta]
Exome VariantVTCN1
dbVarVTCN1
ClinVarVTCN1
snp3D : Map Gene to Disease79679
DGIdb (Curated mutations)VTCN1
DGIdb (Drug Gene Interaction db)VTCN1
General knowledge
Homologs : HomoloGeneVTCN1
Homology/Alignments : Family Browser (UCSC)VTCN1
Phylogenetic Trees/Animal Genes : TreeFamVTCN1
Chemical/Protein Interactions : CTD79679
Chemical/Pharm GKB GenePA142670611
Clinical trialVTCN1
Cancer Resource (Charite)ENSG00000134258
Other databases
Probes
Litterature
PubMed50 Pubmed reference(s) in Entrez
CoreMineVTCN1
GoPubMedVTCN1
iHOPVTCN1

Bibliography

Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family.
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B7-H4, a molecule of the B7 family, negatively regulates T cell immunity.
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PMID 12818165
 
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The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation.
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PMID 15878339
 
B7-h4 is highly expressed in ductal and lobular breast cancer.
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Differential gene expression profiles between tumor biopsies and short-term primary cultures of ovarian serous carcinomas: identification of novel molecular biomarkers for early diagnosis and therapy.
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B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival.
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Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (27) : 10391-10396.
PMID 16798883
 
Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells.
Kryczek I, Wei S, Zou L, Zhu G, Mottram P, Xu H, Chen L, Zou W
Journal of immunology (Baltimore, Md. : 1950). 2006 ; 177 (1) : 40-44.
PMID 16785496
 
B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma.
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B7-h4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer.
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B7-H3 and B7-H4 expression in non-small-cell lung cancer.
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B7-H4 overexpression in ovarian tumors.
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PMID 16256178
 
The new B7s: playing a pivotal role in tumor immunity.
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PMID 17414316
 
Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma.
Kryczek I, Wei S, Zhu G, Myers L, Mottram P, Cheng P, Chen L, Coukos G, Zou W
Cancer research. 2007 ; 67 (18) : 8900-8905.
PMID 17875732
 
B7-H4 (DD-O110) is overexpressed in high risk uterine endometrioid adenocarcinomas and inversely correlated with tumor T-cell infiltration.
Miyatake T, Tringler B, Liu W, Liu SH, Papkoff J, Enomoto T, Torkko KC, Dehn DL, Swisher A, Shroyer KR
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PMID 17509674
 
B7-h4 expression in a range of breast pathology: correlation with tumor T-cell infiltration.
Mugler KC, Singh M, Tringler B, Torkko KC, Liu W, Papkoff J, Shroyer KR
Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry. 2007 ; 15 (4) : 363-370.
PMID 18091377
 
B7-H4 is over-expressed in early-stage ovarian cancer and is independent of CA125 expression.
Simon I, Katsaros D, Rigault de la Longrais I, Massobrio M, Scorilas A, Kim NW, Sarno MJ, Wolfert RL, Diamandis EP
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PMID 17498784
 
Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer.
Simon I, Liu Y, Krall KL, Urban N, Wolfert RL, Kim NW, McIntosh MW
Gynecologic oncology. 2007 ; 106 (1) : 112-118.
PMID 17490732
 
B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome.
Zang X, Thompson RH, Al-Ahmadie HA, Serio AM, Reuter VE, Eastham JA, Scardino PT, Sharma P, Allison JP
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PMID 18042703
 
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Contributor(s)

Written02-2008Panduka Samarawardana, Kenneth R Shroyer
Department of Pathology, University of Colorado at Denver and Health Sciences Center, (PS); Department of Pathology, Stony Brook University Medical Center, Aurora, CO 80045, USA (KRS)

Citation

This paper should be referenced as such :
Samarawardana, P ; Shroyer, KR
VTCN1 (V-set domain containing T cell activation inhibitor 1)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(6):452-454.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/VTCN1ID44144ch1p13.html

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indexed on : Thu Dec 4 15:15:32 CET 2014

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