Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

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

Written2008-02Panduka Samarawardana, Kenneth R Shroyer
Department of Pathology, University of Colorado at Denver, Health Sciences Center, (PS); Department of Pathology, Stony Brook University Medical Center, Aurora, CO 80045, USA (KRS)

(Note : for Links provided by Atlas : click)


Alias (NCBI)B7H4
HGNC Alias symbB7-H4
HGNC Alias nameB7 family member, H4
 B7 superfamily member 1
LocusID (NCBI) 79679
Atlas_Id 44144
Location 1p13.1  [Link to chromosome band 1p13]
Location_base_pair Starts at 117143587 and ends at 117210927 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping VTCN1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
VTCN1 (1p13.1)::NUP88 (17p13.2)VTCN1 (1p13.1)::PTGFRN (1p13.1)


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).


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 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.


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.
Bignotti E, Tassi RA, Calza S, Ravaggi A, Romani C, Rossi E, Falchetti M, Odicino FE, Pecorelli S, Santin AD
Gynecologic oncology. 2006 ; 103 (2) : 405-416.
PMID 16725184
Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family.
Choi IH, Zhu G, Sica GL, Strome SE, Cheville JC, Lau JS, Zhu Y, Flies DB, Tamada K, Chen L
Journal of immunology (Baltimore, Md. : 1950). 2003 ; 171 (9) : 4650-4654.
PMID 14568939
The B7 family of immune-regulatory ligands.
Collins M, Ling V, Carreno BM
Genome biology. 2005 ; 6 (6) : page 223.
PMID 15960813
The new B7s: playing a pivotal role in tumor immunity.
Flies DB, Chen L
Journal of immunotherapy (Hagerstown, Md. : 1997). 2007 ; 30 (3) : 251-260.
PMID 17414316
B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival.
Krambeck AE, Thompson RH, Dong H, Lohse CM, Park ES, Kuntz SM, Leibovich BC, Blute ML, Cheville JC, Kwon ED
Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (27) : 10391-10396.
PMID 16798883
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 expression identifies a novel suppressive macrophage population in human ovarian carcinoma.
Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, Brumlik M, Cheng P, Curiel T, Myers L, Lackner A, Alvarez X, Ochoa A, Chen L, Zou W
The Journal of experimental medicine. 2006 ; 203 (4) : 871-881.
PMID 16606666
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
Gynecologic oncology. 2007 ; 106 (1) : 119-127.
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
B7S1, a novel B7 family member that negatively regulates T cell activation.
Prasad DV, Richards S, Mai XM, Dong C
Immunity. 2003 ; 18 (6) : 863-873.
PMID 12818166
The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation.
Salceda S, Tang T, Kmet M, Munteanu A, Ghosh M, Macina R, Liu W, Pilkington G, Papkoff J
Experimental cell research. 2005 ; 306 (1) : 128-141.
PMID 15878339
B7-H4, a molecule of the B7 family, negatively regulates T cell immunity.
Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, Chapoval AI, Flies DB, Bajorath J, Chen L
Immunity. 2003 ; 18 (6) : 849-861.
PMID 12818165
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
Gynecologic oncology. 2007 ; 106 (2) : 334-341.
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-h4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer.
Simon I, Zhuo S, Corral L, Diamandis EP, Sarno MJ, Wolfert RL, Kim NW
Cancer research. 2006 ; 66 (3) : 1570-1575.
PMID 16452214
B7-H3 and B7-H4 expression in non-small-cell lung cancer.
Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK, Wang X
Lung cancer (Amsterdam, Netherlands). 2006 ; 53 (2) : 143-151.
PMID 16782226
B7-H4 overexpression in ovarian tumors.
Tringler B, Liu W, Corral L, Torkko KC, Enomoto T, Davidson S, Lucia MS, Heinz DE, Papkoff J, Shroyer KR
Gynecologic oncology. 2006 ; 100 (1) : 44-52.
PMID 16256178
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
Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (49) : 19458-19463.
PMID 18042703


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 journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)VTCN1   28873
Entrez_Gene (NCBI)VTCN1    V-set domain containing T cell activation inhibitor 1
AliasesB7-H4; B7H4; B7S1; B7X; 
B7h.5; PRO1291; VCTN1
GeneCards (Weizmann)VTCN1
Ensembl hg19 (Hinxton)ENSG00000134258 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000134258 [Gene_View]  ENSG00000134258 [Sequence]  chr1:117143587-117210927 [Contig_View]  VTCN1 [Vega]
ICGC DataPortalENSG00000134258
TCGA cBioPortalVTCN1
Genatlas (Paris)VTCN1
SOURCE (Princeton)VTCN1
Genetics Home Reference (NIH)VTCN1
Genomic and cartography
GoldenPath hg38 (UCSC)VTCN1  -     chr1:117143587-117210927 -  1p13.1-p12   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)VTCN1  -     1p13.1-p12   [Description]    (hg19-Feb_2009)
GoldenPathVTCN1 - 1p13.1-p12 [CytoView hg19]  VTCN1 - 1p13.1-p12 [CytoView hg38]
Genome Data Viewer NCBIVTCN1 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AI686571 AK026071 AK225413 AK303466 AK310812
RefSeq transcript (Entrez)NM_001253849 NM_001253850 NM_024626
Consensus coding sequences : CCDS (NCBI)VTCN1
Gene ExpressionVTCN1 [ NCBI-GEO ]   VTCN1 [ EBI - ARRAY_EXPRESS ]   VTCN1 [ SEEK ]   VTCN1 [ MEM ]
Gene Expression Viewer (FireBrowse)VTCN1 [ Firebrowse - Broad ]
GenevisibleExpression of VTCN1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)79679
GTEX Portal (Tissue expression)VTCN1
Human Protein AtlasENSG00000134258-VTCN1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ7Z7D3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ7Z7D3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ7Z7D3
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)   
Domains : Interpro (EBI)Ig-like_dom    Ig-like_dom_sf    Ig-like_fold    Ig_sub    Ig_V-set   
Domain families : Pfam (Sanger)V-set (PF07686)   
Domain families : Pfam (NCBI)pfam07686   
Domain families : Smart (EMBL)IG (SM00409)  
Conserved Domain (NCBI)VTCN1
PDB Europe4GOS   
Structural Biology KnowledgeBase4GOS   
SCOP (Structural Classification of Proteins)4GOS   
CATH (Classification of proteins structures)4GOS   
AlphaFold pdb e-kbQ7Z7D3   
Human Protein Atlas [tissue]ENSG00000134258-VTCN1 [tissue]
Protein Interaction databases
IntAct (EBI)Q7Z7D3
Ontologies - Pathways
Ontology : AmiGOresponse to protozoan  regulation of cytokine production  adaptive immune response  molecular_function  signaling receptor binding  external side of plasma membrane  external side of plasma membrane  integral component of membrane  positive regulation of interleukin-2 production  positive regulation of T cell proliferation  negative regulation of T cell proliferation  negative regulation of apoptotic process  T cell receptor signaling pathway  negative regulation of T cell activation  
Ontology : EGO-EBIresponse to protozoan  regulation of cytokine production  adaptive immune response  molecular_function  signaling receptor binding  external side of plasma membrane  external side of plasma membrane  integral component of membrane  positive regulation of interleukin-2 production  positive regulation of T cell proliferation  negative regulation of T cell proliferation  negative regulation of apoptotic process  T cell receptor signaling pathway  negative regulation of T cell activation  
Pathways : KEGGCell adhesion molecules (CAMs)   
NDEx NetworkVTCN1
Atlas of Cancer Signalling NetworkVTCN1
Wikipedia pathwaysVTCN1
Orthology - Evolution
GeneTree (enSembl)ENSG00000134258
Phylogenetic Trees/Animal Genes : TreeFamVTCN1
Homologs : HomoloGeneVTCN1
Homology/Alignments : Family Browser (UCSC)VTCN1
Gene fusions - Rearrangements
Fusion : MitelmanVTCN1::NUP88 [1p13.1/17p13.2]  
Fusion : MitelmanVTCN1::PTGFRN [1p13.1/1p13.1]  
Fusion : QuiverVTCN1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerVTCN1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)VTCN1
Exome Variant ServerVTCN1
GNOMAD BrowserENSG00000134258
Varsome BrowserVTCN1
ACMGVTCN1 variants
Genomic Variants (DGV)VTCN1 [DGVbeta]
DECIPHERVTCN1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisVTCN1 
ICGC Data PortalVTCN1 
TCGA Data PortalVTCN1 
Broad Tumor PortalVTCN1
OASIS PortalVTCN1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICVTCN1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DVTCN1
Mutations and Diseases : HGMDVTCN1
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)VTCN1
DoCM (Curated mutations)VTCN1
CIViC (Clinical Interpretations of Variants in Cancer)VTCN1
NCG (London)VTCN1
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry VTCN1
NextProtQ7Z7D3 [Medical]
Target ValidationVTCN1
Huge Navigator VTCN1 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDVTCN1
Pharm GKB GenePA142670611
Clinical trialVTCN1
DataMed IndexVTCN1
PubMed145 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Oct 8 21:30:39 CEST 2021

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us