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STAG2 (Stromal Antigen 2)

Written2013-09Suning Chen, Stefan Nagel, Hans G Drexler, Roderick AF MacLeod
Jiangsu Institute of Hematology, Key Laboratory of Thrombosis, Hemostasis of Ministry of Health, the First Affiliated Hospital of Soochow University, Suzhou, P R China (SC); Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Germany (SN, HGD, RAFM)

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)SA-2
SCC3B
SA2
HGNC (Hugo) STAG2
LocusID (NCBI) 10735
Atlas_Id 52377
Location Xq25  [Link to chromosome band Xq25]
Location_base_pair Starts at 123094410 and ends at 123236505 bp from pter ( according to hg19-Feb_2009)  [Mapping STAG2.png]
Fusion genes
(updated 2016)
LSM14A (19q13.11) / STAG2 (Xq25)STAG2 (Xq25) / C16orf45 (16p13.11)STAG2 (Xq25) / CMC4 (Xq28)
STAG2 (Xq25) / EIF3A (10q26.11)STAG2 (Xq25) / GRIA3 (Xq25)STAG2 (Xq25) / STAG2 (Xq25)
STAG2 (Xq25) / XIAP (Xq25)XIAP (Xq25) / STAG2 (Xq25)cytochrome_b () / STAG2 (Xq25)

DNA/RNA

 
  Figure 1. Clustering of GATA3 TFBS in STAG2 regulatory region. Schema showing multiple GATA3 TFBS present in the regulatory intron of STAG2. For additional TFBS see: SABiosciences
Description The STAG2 gene consists of 35 exons spanning 142 Kbp, located at chromosome Xq25.
Transcription Transcription takes place in a centromere --> telomere orientation (plus strand). Transcription of STAG2 gene generates 19 different mRNA transcripts, the longest is 6045 bp containing 34 exons (ENST00000371160).
There are multiple transcription factor binding sites (TFBS) for GATA3 present in the regulatory first intron of STAG2 summarized above (Fig. 1).
Pseudogene There are no known pseudogenes.

Protein

Description The STAG2 gene encodes two alternative isoforms:
- A: Q8N3U4-1, 1231 aa, 141.3 KDa
- B: Q8N3U4-2, 1268 aa, 145.7 KDa
 
  Figure 2. Domain structure of STAG2 and amino acid sequence.
Expression STAG2 mRNA is expressed in cells from most tissues. Peak expression occurs in T-cell and early erythroid compartments, and in the uterus. Lowest expression is found in brain, heart, liver, lung and testis. STAG2 is also overexpressed in T-/B-cell acute lymphoblastic leukemia (ALL) and in other hematopoietic neoplasias, followed by small cell lung cancer, neuroblastoma and medulloblastoma.
It has been reported that the expression of STAG2 protein is lost in some cancer types such as glioblastoma, Ewing's sarcoma, and melanoma (Solomon et al., 2011), colorectal carcinomas, gastric carcinomas and prostate carcinomas (Kim et al., 2012).
Localisation Nucleus albeit reportedly with transmembrane potential.
Function STAG2 forms the cohesin complex together with SMC1, SMC3, and SCC1. The cohesin complex is a ring-like structure and is required for cohesion of sister chromatids after DNA replication. The complex is cleaved at the metaphase-anaphase transition and dissociates from chromatin for separation of sister chromatids (Xiao et al., 2011). While STAG2 mediates centromere cohesion, that of telomeres is mediated by the homologous STAG1 (Canudas et al., 2009; Remeseiro et al., 2012).
Cohesin also plays a major part in the organization of interphase chromatin, including the orchestration of gene expression in relation to cell cycle where STAG2 also plays a key role along with the universal transcriptional repressor CCCTC-binding factor (CTCF). CTCF-cohesin interactions require contact between STAG2 and C-terminal CTCF which facilitate recruitment of other cohesion complex proteins and formation of the cohesion ring. This interaction is also needed for CTCF to function as a transcriptional insulator.
Homology Two paralogs are known: STAG1 and STAG3 which can replace STAG2 in the cohesion complex.
 

Mutations

Note Recurrent STAG2 gene mutations were reported in glioblastoma, melanoma and Ewing's sarcoma (Solomon et al., 2011). Recently, STAG2 gene was found frequently mutated in myeloid neoplasms, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), chronic myelogenous leukemia (CML) and classical myeloproliferative neoplasms (MPN) (Kon et al., 2013). Other studies observed lower frequencies of STAG2 mutation (Chung et al., 2012; Kim et al., 2012).
It remains unclear whether mutations affecting STAG2 operate to induce aneuploidy (Solomon et al., 2011; Kolodner et al., 2011), or simply to abrogate expression (Rocquain et al., 2010; Kon et al., 2013).

Implicated in

Note
Entity Myeloid neoplasms
Note Mutation and deletion of the STAG2 gene was identified in 5.8% (13/224) of MDS, 10.2% (9/88) of CMML, 6.4% (10/157) of AML, 3.1% (2/64) of CML, and 1.3% (1/77) of MPN: the STAG2 alterations were mostly exclusive with alterations involving other components of cohesin complex (SMC1, SMC3, and RAD21) and were significantly associated with mutations in TET2, ASXL1, and EZH2 (Kon et al., 2013).
  
Entity t(X;11)(q25;p13)
Disease T-ALL: only two T-ALL cell lines described so far.
Cytogenetics t(X;11)(q25;p13) in MOLT-14 cells and t(X;1;11)(q25;p13;p13) in PER-117 cells. The rearrangement is fully cryptic (see below).
 
Figure 4. Cytogenetic analysis of t(X;11) effecting juxtaposition of STAG2 and LMO2. Image shows FISH analysis of t(X;11)(q25;p13) in a T-ALL cell line (DSM ACC 437). Note that this translocation is cryptic in G-banding (Fig. A). FISH using BAC and fosmid clones (Fig. B, C) places breakpoints in MOLT-14 and another T-ALL cell line PER-117, both inside the first (regulatory) intron of STAG2. In both cell lines expression of STAG2 is lost, attributable to divestment of this region which includes a deeply conserved cluster of regulatory motifs, including transcription factor binding sites and DNaseI sensitive sites. Upregulation of LMO2 in both cell lines occurred, concomitant with acquisition of the upstream STAG2 region. Fig. D: Genomic map of Xq25 showing breakpoints in regulatory region in relation to clones used for FISH. Figure redrawn and updated from Chen et al. (2011).
Oncogenesis t(X;11)(q25;p13) results in simultaneous upregulation of LMO2 and silencing of STAG2 by juxtaposition of the far upstream region of LMO2 with the first regulatory intron of STAG2 (Chen et al., 2011).
  

Bibliography

Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, respectively, in human cells.
Canudas S, Smith S.
J Cell Biol. 2009 Oct 19;187(2):165-73. doi: 10.1083/jcb.200903096. Epub 2009 Oct 12.
PMID 19822671
 
Novel non-TCR chromosome translocations t(3;11)(q25;p13) and t(X;11)(q25;p13) activating LMO2 by juxtaposition with MBNL1 and STAG2.
Chen S, Nagel S, Schneider B, Kaufmann M, Meyer C, Zaborski M, Kees UR, Drexler HG, MacLeod RA.
Leukemia. 2011 Oct;25(10):1632-5. doi: 10.1038/leu.2011.119. Epub 2011 Jun 7.
PMID 21647158
 
Somatic mutation of STAG2, an aneuploidy-related gene, is rare in acute leukemias.
Chung NG, Kim MS, Yoo NJ, Lee SH.
Leuk Lymphoma. 2012 Jun;53(6):1234-5. doi: 10.3109/10428194.2011.645819. Epub 2012 Jan 3.
PMID 22132872
 
Condensin and cohesin: more than chromosome compactor and glue.
Hagstrom KA, Meyer BJ.
Nat Rev Genet. 2003 Jul;4(7):520-34. (REVIEW)
PMID 12838344
 
Mutational and expressional analyses of STAG2 gene in solid cancers.
Kim MS, Kim SS, Je EM, Yoo NJ, Lee SH.
Neoplasma. 2012;59(5):524-9. doi: 10.4149/neo_2012_067.
PMID 22668012
 
Cancer. Aneuploidy drives a mutator phenotype in cancer.
Kolodner RD, Cleveland DW, Putnam CD.
Science. 2011 Aug 19;333(6045):942-3. doi: 10.1126/science.1211154.
PMID 21852477
 
Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms.
Kon A, Shih LY, Minamino M, Sanada M, Shiraishi Y, Nagata Y, Yoshida K, Okuno Y, Bando M, Nakato R, Ishikawa S, Sato-Otsubo A, Nagae G, Nishimoto A, Haferlach C, Nowak D, Sato Y, Alpermann T, Nagasaki M, Shimamura T, Tanaka H, Chiba K, Yamamoto R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Nakamaki T, Ishiyama K, Nolte F, Hofmann WK, Miyawaki S, Chiba S, Mori H, Nakauchi H, Koeffler HP, Aburatani H, Haferlach T, Shirahige K, Miyano S, Ogawa S.
Nat Genet. 2013 Oct;45(10):1232-7. doi: 10.1038/ng.2731. Epub 2013 Aug 18.
PMID 23955599
 
Cohesin, a chromatin engagement ring.
Remeseiro S, Losada A.
Curr Opin Cell Biol. 2013 Feb;25(1):63-71. doi: 10.1016/j.ceb.2012.10.013. Epub 2012 Dec 6. (REVIEW)
PMID 23219370
 
Alteration of cohesin genes in myeloid diseases.
Rocquain J, Gelsi-Boyer V, Adelaide J, Murati A, Carbuccia N, Vey N, Birnbaum D, Mozziconacci MJ, Chaffanet M.
Am J Hematol. 2010 Sep;85(9):717-9. doi: 10.1002/ajh.21798.
PMID 20687102
 
Mutational inactivation of STAG2 causes aneuploidy in human cancer.
Solomon DA, Kim T, Diaz-Martinez LA, Fair J, Elkahloun AG, Harris BT, Toretsky JA, Rosenberg SA, Shukla N, Ladanyi M, Samuels Y, James CD, Yu H, Kim JS, Waldman T.
Science. 2011 Aug 19;333(6045):1039-43. doi: 10.1126/science.1203619.
PMID 21852505
 
Specific sites in the C terminus of CTCF interact with the SA2 subunit of the cohesin complex and are required for cohesin-dependent insulation activity.
Xiao T, Wallace J, Felsenfeld G.
Mol Cell Biol. 2011 Jun;31(11):2174-83. doi: 10.1128/MCB.05093-11. Epub 2011 Mar 28.
PMID 21444719
 

Citation

This paper should be referenced as such :
Chen, S ; Nagel, S ; Drexler, HG ; MacLeod, RAF
STAG2 (Stromal Antigen 2)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(4):272-275.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/STAG2ID52377chXq25.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  Chronic Myelomonocytic Leukemia (CMML)


External links

Nomenclature
HGNC (Hugo)STAG2   11355
LRG (Locus Reference Genomic)LRG_782
Cards
AtlasSTAG2ID52377chXq25
Entrez_Gene (NCBI)STAG2  10735  stromal antigen 2
AliasesSA-2; SA2; SCC3B; bA517O1.1
GeneCards (Weizmann)STAG2
Ensembl hg19 (Hinxton)ENSG00000101972 [Gene_View]  chrX:123094410-123236505 [Contig_View]  STAG2 [Vega]
Ensembl hg38 (Hinxton)ENSG00000101972 [Gene_View]  chrX:123094410-123236505 [Contig_View]  STAG2 [Vega]
ICGC DataPortalENSG00000101972
TCGA cBioPortalSTAG2
AceView (NCBI)STAG2
Genatlas (Paris)STAG2
WikiGenes10735
SOURCE (Princeton)STAG2
Genetics Home Reference (NIH)STAG2
Genomic and cartography
GoldenPath hg19 (UCSC)STAG2  -     chrX:123094410-123236505 +  Xq25   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)STAG2  -     Xq25   [Description]    (hg38-Dec_2013)
EnsemblSTAG2 - Xq25 [CytoView hg19]  STAG2 - Xq25 [CytoView hg38]
Mapping of homologs : NCBISTAG2 [Mapview hg19]  STAG2 [Mapview hg38]
OMIM300826   
Gene and transcription
Genbank (Entrez)AA428995 AK026678 AK098737 AK298633 AK313559
RefSeq transcript (Entrez)NM_001042749 NM_001042750 NM_001042751 NM_001282418 NM_006603
RefSeq genomic (Entrez)NC_000023 NC_018934 NG_033796 NT_011786 NW_004929446
Consensus coding sequences : CCDS (NCBI)STAG2
Cluster EST : UnigeneHs.624663 [ NCBI ]
CGAP (NCI)Hs.624663
Alternative Splicing GalleryENSG00000101972
Gene ExpressionSTAG2 [ NCBI-GEO ]   STAG2 [ EBI - ARRAY_EXPRESS ]   STAG2 [ SEEK ]   STAG2 [ MEM ]
Gene Expression Viewer (FireBrowse)STAG2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)10735
GTEX Portal (Tissue expression)STAG2
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8N3U4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8N3U4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8N3U4
Splice isoforms : SwissVarQ8N3U4
PhosPhoSitePlusQ8N3U4
Domaine pattern : Prosite (Expaxy)SCD (PS51425)   
Domains : Interpro (EBI)ARM-type_fold    SCD    STAG   
Domain families : Pfam (Sanger)STAG (PF08514)   
Domain families : Pfam (NCBI)pfam08514   
Conserved Domain (NCBI)STAG2
DMDM Disease mutations10735
Blocks (Seattle)STAG2
PDB (SRS)4PJU    4PJW    4PK7   
PDB (PDBSum)4PJU    4PJW    4PK7   
PDB (IMB)4PJU    4PJW    4PK7   
PDB (RSDB)4PJU    4PJW    4PK7   
Structural Biology KnowledgeBase4PJU    4PJW    4PK7   
SCOP (Structural Classification of Proteins)4PJU    4PJW    4PK7   
CATH (Classification of proteins structures)4PJU    4PJW    4PK7   
SuperfamilyQ8N3U4
Human Protein AtlasENSG00000101972
Peptide AtlasQ8N3U4
HPRD05077
IPIIPI00552978   IPI00470883   IPI01013030   IPI00641720   IPI00647430   IPI00642251   IPI00640203   IPI00640730   IPI00794765   IPI00852883   IPI00893523   
Protein Interaction databases
DIP (DOE-UCLA)Q8N3U4
IntAct (EBI)Q8N3U4
FunCoupENSG00000101972
BioGRIDSTAG2
STRING (EMBL)STAG2
ZODIACSTAG2
Ontologies - Pathways
QuickGOQ8N3U4
Ontology : AmiGOchromosome, centromeric region  chromatin  protein binding  nucleus  nucleus  nucleoplasm  chromosome  nucleolus  cytosol  plasma membrane  sister chromatid cohesion  sister chromatid cohesion  mitotic nuclear division  actin cytoskeleton  membrane  protein sumoylation  negative regulation of DNA endoreduplication  intermediate filament cytoskeleton  cell division  meiotic cell cycle  
Ontology : EGO-EBIchromosome, centromeric region  chromatin  protein binding  nucleus  nucleus  nucleoplasm  chromosome  nucleolus  cytosol  plasma membrane  sister chromatid cohesion  sister chromatid cohesion  mitotic nuclear division  actin cytoskeleton  membrane  protein sumoylation  negative regulation of DNA endoreduplication  intermediate filament cytoskeleton  cell division  meiotic cell cycle  
Pathways : KEGGCell cycle   
REACTOMEQ8N3U4 [protein]
REACTOME PathwaysR-HSA-2468052 Establishment of Sister Chromatid Cohesion [pathway]
REACTOME PathwaysR-HSA-2467813 Separation of Sister Chromatids [pathway]
REACTOME PathwaysR-HSA-2500257 Resolution of Sister Chromatid Cohesion [pathway]
REACTOME PathwaysR-HSA-1221632 Meiotic synapsis [pathway]
REACTOME PathwaysR-HSA-2470946 Cohesin Loading onto Chromatin [pathway]
REACTOME PathwaysR-HSA-3108214 SUMOylation of DNA damage response and repair proteins [pathway]
NDEx NetworkSTAG2
Atlas of Cancer Signalling NetworkSTAG2
Wikipedia pathwaysSTAG2
Orthology - Evolution
OrthoDB10735
GeneTree (enSembl)ENSG00000101972
Phylogenetic Trees/Animal Genes : TreeFamSTAG2
HOVERGENQ8N3U4
HOGENOMQ8N3U4
Homologs : HomoloGeneSTAG2
Homology/Alignments : Family Browser (UCSC)STAG2
Gene fusions - Rearrangements
Fusion : MitelmanSTAG2/C16orf45 [Xq25/16p13.11]  
Fusion: TCGASTAG2 Xq25 C16orf45 16p13.11 LUAD
Fusion: TCGASTAG2 Xq25 GRIA3 Xq25 LUAD
Fusion: TCGASTAG2 Xq25 MTCP1NB BRCA
Fusion: TCGASTAG2 Xq25 XIAP Xq25 BRCA
Fusion Cancer (Beijing)cytochrome_b [STAG2]  -  Xq25 [FUSC000404]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSTAG2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)STAG2
dbVarSTAG2
ClinVarSTAG2
1000_GenomesSTAG2 
Exome Variant ServerSTAG2
ExAC (Exome Aggregation Consortium)STAG2 (select the gene name)
Genetic variants : HAPMAP10735
Genomic Variants (DGV)STAG2 [DGVbeta]
DECIPHER (Syndromes)X:123094410-123236505  ENSG00000101972
CONAN: Copy Number AnalysisSTAG2 
Mutations
ICGC Data PortalSTAG2 
TCGA Data PortalSTAG2 
Broad Tumor PortalSTAG2
OASIS PortalSTAG2 [ Somatic mutations - Copy number]
Cancer Gene: CensusSTAG2 
Somatic Mutations in Cancer : COSMICSTAG2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSTAG2
intOGen PortalSTAG2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch STAG2
DgiDB (Drug Gene Interaction Database)STAG2
DoCM (Curated mutations)STAG2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)STAG2 (select a term)
intoGenSTAG2
NCG5 (London)STAG2
Cancer3DSTAG2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM300826   
Orphanet
MedgenSTAG2
Genetic Testing Registry STAG2
NextProtQ8N3U4 [Medical]
TSGene10735
GENETestsSTAG2
Huge Navigator STAG2 [HugePedia]
snp3D : Map Gene to Disease10735
BioCentury BCIQSTAG2
ClinGenSTAG2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD10735
Chemical/Pharm GKB GenePA36177
Clinical trialSTAG2
Miscellaneous
canSAR (ICR)STAG2 (select the gene name)
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=STAG2
Probes
Litterature
PubMed66 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSTAG2
EVEXSTAG2
GoPubMedSTAG2
iHOPSTAG2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Jan 12 11:34:50 CET 2017

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