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PRAME (Preferentially Expressed Antigen In Melanoma)

Written2014-04Joel Fulton, David M Heery
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMAPE
Alias_symbol (synonym)CT130
Other aliasOIP-4
OIP4
HGNC (Hugo) PRAME
LocusID (NCBI) 23532
Atlas_Id 41828
Location 22q11.22  [Link to chromosome band 22q11]
Location_base_pair Starts at 22890118 and ends at 22900174 bp from pter ( according to hg19-Feb_2009)  [Mapping PRAME.png]
Fusion genes
(updated 2016)
PRAME (22q11.22) / ACO2 (22q13.2)PRAME (22q11.22) / GDI2 (10p15.1)PRAME (22q11.22) / HDLBP (2q37.3)

DNA/RNA

Note PRAME is a member of a multigene family present in humans and other mammals. It was originally identified as a gene encoding a novel cancer-testis antigen that is over expressed in melanoma (Ikeda et al., 1997). Its evolution is consistent with adaptive (positive) selection similar to gene clusters involved in immunity and reproduction, such as the NALP family (Tian et al., 2009). Expression of PRAME has been shown to be regulated by hypomethylation of its promoter in AML and CML (Ortmann et al., 2008; Roman-Gomez et al., 2007).
Description The gene is encoded on the reverse strand of chromosome 22 (22q11.22) covering a region of approximately 12 kilobases and is within the human immunoglobulin lambda gene locus (Kawasaki et al., 1997). This locus contains a large number of Vl gene segments which code for production of l light chains during B cell development and several other non-immunoglobulin genes, for example, tandem Suppressor of Hairy Wing genes (SUHW1/ZNF280A and SUHW2/ZNF280B) and a gene encoding a putative membrane glycoprotein (POM121L1).
Transcription The NCBI database annotates five PRAME mRNA transcripts ranging from 2.1-2.7 kb in length (2141, 2162, 2197, 2220, 2776 bases) which encode the same protein.
Transcript (Including UTRs):
- Position: chr22:22890123-22896603, Size: 6481, Total exon count: 4
- Strand: -
Coding region:
- Position: chr22:22890489-22893484, Size: 2996, Coding exon count: 3
Pseudogene The gene seems to have undergone multiple duplications during hominid evolution, and at least 22 PRAME-like genes and 10 pseudogenes have been identified in the human genome (Birtle et al., 2005).

Protein

Note PRAME is a leucine-rich protein of which 21.8% of residues are leucine or isoleucine.
 
  Predicted domain structure of the human PRAME sequence highlighting Leucine Rich Repeats (LRRs). The LRRs are numbered and indicated by the blue arrows; residues conserved in typical LRRs are highlighted in bold. The black boxes indicate regions predicted to have a high probability of α-helicity, and two predicted NLS sequences are underlined. The boxed area in red is a region implicated in interaction with retinoic acid receptors (Wadelin et al., 2010).
Description NP_006106 : Predicted 509 amino acid, 58 kDa protein.
Expression PRAME is expressed at low levels in a few normal tissues, at intermediate level in adrenals, ovary, and endometrium and at high level in the testes. It has been shown to be overexpressed in malignant cells including the vast majority of primary and metastatic melanomas and is recognized by cytolytic T lymphocytes (Haqq et al., 2005). In PRAME-negative leukaemias the gene can be induced by demethylating agents (Sigalotti et al., 2004).
Localisation The protein has been observed to localise to both the nucleus and perinuclear regions (Tajeddine et al., 2005). PRAME contains several candidate nuclear localisation signal (NLS) sequences (See Figure).
Function Human PRAME and its paralogues are related to LRR family proteins, some of which are known to have functions in cell immunity and signal transduction. It has been suggested that, like TLRs, PRAME may be upregulated in response to encounters with microbial pathogens, and may be involved in targeting intracellular PAMPs to the Golgi for ubiquitylation and processing. (Wadelin et al., 2013). PRAME has been reported to function as a repressor of retinoic acid (RA) signalling through interactions with retinoic acid receptors (RARs) and repression of the RARb2 gene (Epping et al., 2005; Epping et al., 2007).
Homology Sequence homology and structural predictions suggest that PRAME is related to the leucine-rich repeat (LRR) family of proteins such as the Toll-like receptors. The Oogenesins 1-4 also show considerable homology to PRAME and PRAME family members (Dade et al., 2003).

Mutations

Note Some listed in COSMIC.

Implicated in

Note
  
Entity Melanoma
Note High levels of PRAME mRNA are present in the majority of primary and metastatic melanomas (88% and 95% respectively) (Haqq et al., 2005), while being absent in normal haematopoietic tissues including bone marrow (Oehler et al., 2009; Radich et al., 2006; Steinbach et al., 2002; van Baren et al., 1998).
  
  
Entity Acute and chronic leukaemia, non Hodgkins lymphomas
Note Numerous studies have reported highly elevated levels of PRAME in both acute and chronic leukaemias and non Hodgkin's lymphomas (van Baren et al., 1998; Matsushita et al., 2001; Oehler et al., 2009; Qin et al., 2009; Radich et al., 2006; Santamaria et al., 2008). PRAME expression has been suggested to be predicator for a good clinical outcome in childhood acute lymphoblastic leukemia in addition to being a target for immunotherapy, and biomarker for the monitoring of minimal residual disease (Abdelmalak et al., 2014).
  
  
Entity Neuroblastoma
Note PRAME is expressed in high-stage neuroblastoma and associated with poor outcome (Oberthuer et al., 2004).
  
  
Entity Breast cancer
Note PRAME is expressed in advanced breast cancer and has been shown to be an independent prognostic factor for shortened disease-free survival (Doolan et al., 2008).
  
  
Entity Ovarian adenocarcinoma
Note PRAME was found to be a biomarker and prognostic factor for patients with stage III serous ovarian adenocarcinomas (Partheen et al., 2008).
  
  
Entity Lung squamous cell carcinoma
Note Northern blot analysis demonstrated that high proportion of positive tumours were shown to express PRAME (Ikeda et al., 1997).
  
  
Entity Head and neck cancer
Note Reverse-transcriptase polymerase chain reaction (RT-PCR) showed high expression of the gene coding for the tumor antigen PRAME in surgical samples of the tumors, margins, and lymph nodes from patients with a diagnosis of head and neck carcinoma (Figueiredo et al., 2006).
  
  
Entity Neurological neoplasms
Note PRAME has been identified as a potential CT antigen for medulloblastoma (Boon et al., 2003) and is universally expressed in high-stage neuroblastoma, and has been associated with poor outcome (Oberthuer et al., 2004).
  

Bibliography

PRAME gene expression in childhood acute lymphoblastic leukemia: impact on prognosis.
Abdelmalak CA, Yahya RS, Elghannam DM, El-Khadragy AE, Abd El Messih HM.
Clin Lab. 2014;60(1):55-61.
PMID 24600975
 
Duplication and positive selection among hominin-specific PRAME genes.
Birtle Z, Goodstadt L, Ponting C.
BMC Genomics. 2005 Sep 13;6:120.
PMID 16159394
 
Comparison of medulloblastoma and normal neural transcriptomes identifies a restricted set of activated genes.
Boon K, Edwards JB, Siu IM, Olschner D, Eberhart CG, Marra MA, Strausberg RL, Riggins GJ.
Oncogene. 2003 Oct 23;22(48):7687-94.
PMID 14576832
 
Identification of a new expanding family of genes characterized by atypical LRR domains. Localization of a cluster preferentially expressed in oocyte.
Dade S, Callebaut I, Mermillod P, Monget P.
FEBS Lett. 2003 Dec 18;555(3):533-8.
PMID 14675769
 
Prevalence and prognostic and predictive relevance of PRAME in breast cancer.
Doolan P, Clynes M, Kennedy S, Mehta JP, Crown J, O'Driscoll L.
Breast Cancer Res Treat. 2008 May;109(2):359-65. Epub 2007 Jul 12.
PMID 17624586
 
A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors.
Epping MT, Wang L, Plumb JA, Lieb M, Gronemeyer H, Brown R, Bernards R.
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17777-82. Epub 2007 Oct 29.
PMID 17968018
 
Expression of cancer testis antigens in head and neck squamous cell carcinomas.
Figueiredo DL, Mamede RC, Proto-Siqueira R, Neder L, Silva WA Jr, Zago MA.
Head Neck. 2006 Jul;28(7):614-9.
PMID 16475205
 
The gene expression signatures of melanoma progression.
Haqq C, Nosrati M, Sudilovsky D, Crothers J, Khodabakhsh D, Pulliam BL, Federman S, Miller JR 3rd, Allen RE, Singer MI, Leong SP, Ljung BM, Sagebiel RW, Kashani-Sabet M.
Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6092-7. Epub 2005 Apr 15.
PMID 15833814
 
Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor.
Ikeda H, Lethe B, Lehmann F, van Baren N, Baurain JF, de Smet C, Chambost H, Vitale M, Moretta A, Boon T, Coulie PG.
Immunity. 1997 Feb;6(2):199-208.
PMID 9047241
 
One-megabase sequence analysis of the human immunoglobulin lambda gene locus
Kawasaki K, Minoshima S, Nakato E, Shibuya K, Shintani A, Schmeits JL, Wang J, Shimizu N.
Genome Res. 1997 Mar;7(3):250-61.
PMID 9074928
 
Quantitative monitoring of the PRAME gene for the detection of minimal residual disease in leukaemia.
Matsushita M, Ikeda H, Kizaki M, Okamoto S, Ogasawara M, Ikeda Y, Kawakami Y.
Br J Haematol. 2001 Mar;112(4):916-26.
PMID 11298586
 
The tumor-associated antigen PRAME is universally expressed in high-stage neuroblastoma and associated with poor outcome.
Oberthuer A, Hero B, Spitz R, Berthold F, Fischer M.
Clin Cancer Res. 2004 Jul 1;10(13):4307-13.
PMID 15240516
 
The preferentially expressed antigen in melanoma (PRAME) inhibits myeloid differentiation in normal hematopoietic and leukemic progenitor cells.
Oehler VG, Guthrie KA, Cummings CL, Sabo K, Wood BL, Gooley T, Yang T, Epping MT, Shou Y, Pogosova-Agadjanyan E, Ladne P, Stirewalt DL, Abkowitz JL, Radich JP.
Blood. 2009 Oct 8;114(15):3299-308. doi: 10.1182/blood-2008-07-170282. Epub 2009 Jul 22.
PMID 19625708
 
Aberrant hypomethylation of the cancer-testis antigen PRAME correlates with PRAME expression in acute myeloid leukemia.
Ortmann CA, Eisele L, Nuckel H, Klein-Hitpass L, Fuhrer A, Duhrsen U, Zeschnigk M.
Ann Hematol. 2008 Oct;87(10):809-18. doi: 10.1007/s00277-008-0514-8. Epub 2008 Jun 28.
PMID 18587578
 
Four potential biomarkers as prognostic factors in stage III serous ovarian adenocarcinomas.
Partheen K, Levan K, Osterberg L, Claesson I, Fallenius G, Sundfeldt K, Horvath G.
Int J Cancer. 2008 Nov 1;123(9):2130-7. doi: 10.1002/ijc.23758.
PMID 18709641
 
Expression patterns of WT1 and PRAME in acute myeloid leukemia patients and their usefulness for monitoring minimal residual disease.
Qin Y, Zhu H, Jiang B, Li J, Lu X, Li L, Ruan G, Liu Y, Chen S, Huang X.
Leuk Res. 2009 Mar;33(3):384-90. doi: 10.1016/j.leukres.2008.08.026. Epub 2008 Oct 23.
PMID 18950857
 
Gene expression changes associated with progression and response in chronic myeloid leukemia.
Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, Sawyers C, Shah N, Stock W, Willman CL, Friend S, Linsley PS.
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2794-9. Epub 2006 Feb 13.
PMID 16477019
 
Epigenetic regulation of PRAME gene in chronic myeloid leukemia.
Roman-Gomez J, Jimenez-Velasco A, Agirre X, Castillejo JA, Navarro G, Jose-Eneriz ES, Garate L, Cordeu L, Cervantes F, Prosper F, Heiniger A, Torres A.
Leuk Res. 2007 Nov;31(11):1521-8. Epub 2007 Mar 26.
PMID 17382387
 
The relevance of preferentially expressed antigen of melanoma (PRAME) as a marker of disease activity and prognosis in acute promyelocytic leukemia.
Santamaria C, Chillon MC, Garcia-Sanz R, Balanzategui A, Sarasquete ME, Alcoceba M, Ramos F, Bernal T, Queizan JA, Penarrubia MJ, Giraldo P, San Miguel JF, Gonzalez M.
Haematologica. 2008 Dec;93(12):1797-805. doi: 10.3324/haematol.13214. Epub 2008 Sep 24.
PMID 18815192
 
Intratumor heterogeneity of cancer/testis antigens expression in human cutaneous melanoma is methylation-regulated and functionally reverted by 5-aza-2'-deoxycytidine.
Sigalotti L, Fratta E, Coral S, Tanzarella S, Danielli R, Colizzi F, Fonsatti E, Traversari C, Altomonte M, Maio M.
Cancer Res. 2004 Dec 15;64(24):9167-71.
PMID 15604288
 
PRAME gene expression in childhood acute lymphoblastic leukemia.
Steinbach D, Viehmann S, Zintl F, Gruhn B.
Cancer Genet Cytogenet. 2002 Oct 1;138(1):89-91.
PMID 12419593
 
Tumor-associated antigen preferentially expressed antigen of melanoma (PRAME) induces caspase-independent cell death in vitro and reduces tumorigenicity in vivo.
Tajeddine N, Gala JL, Louis M, Van Schoor M, Tombal B, Gailly P.
Cancer Res. 2005 Aug 15;65(16):7348-55.
PMID 16103086
 
Evolution and functional divergence of NLRP genes in mammalian reproductive systems.
Tian X, Pascal G, Monget P.
BMC Evol Biol. 2009 Aug 14;9:202. doi: 10.1186/1471-2148-9-202.
PMID 19682372
 
Leucine-rich repeat protein PRAME: expression, potential functions and clinical implications for leukaemia.
Wadelin F, Fulton J, McEwan PA, Spriggs KA, Emsley J, Heery DM.
Mol Cancer. 2010 Aug 27;9:226. doi: 10.1186/1476-4598-9-226. (REVIEW)
PMID 20799951
 
PRAME is a golgi-targeted protein that associates with the Elongin BC complex and is upregulated by interferon-gamma and bacterial PAMPs.
Wadelin FR, Fulton J, Collins HM, Tertipis N, Bottley A, Spriggs KA, Falcone FH, Heery DM.
PLoS One. 2013;8(2):e58052. doi: 10.1371/journal.pone.0058052. Epub 2013 Feb 27.
PMID 23460923
 
PRAME, a gene encoding an antigen recognized on a human melanoma by cytolytic T cells, is expressed in acute leukaemia cells.
van Baren N, Chambost H, Ferrant A, Michaux L, Ikeda H, Millard I, Olive D, Boon T, Coulie PG.
Br J Haematol. 1998 Sep;102(5):1376-9.
PMID 9753074
 

Citation

This paper should be referenced as such :
J Fulton, DM Heery
PRAME (Preferentially Expressed Antigen In Melanoma)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(12):941-944.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PRAMEID41828ch22q11.html


External links

Nomenclature
HGNC (Hugo)PRAME   9336
Cards
AtlasPRAMEID41828ch22q11
Entrez_Gene (NCBI)PRAME  23532  preferentially expressed antigen in melanoma
AliasesCT130; MAPE; OIP-4; OIP4
GeneCards (Weizmann)PRAME
Ensembl hg19 (Hinxton)ENSG00000185686 [Gene_View]  chr22:22890118-22900174 [Contig_View]  PRAME [Vega]
Ensembl hg38 (Hinxton)ENSG00000185686 [Gene_View]  chr22:22890118-22900174 [Contig_View]  PRAME [Vega]
ICGC DataPortalENSG00000185686
TCGA cBioPortalPRAME
AceView (NCBI)PRAME
Genatlas (Paris)PRAME
WikiGenes23532
SOURCE (Princeton)PRAME
Genetics Home Reference (NIH)PRAME
Genomic and cartography
GoldenPath hg19 (UCSC)PRAME  -     chr22:22890118-22900174 -  22q11.22   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PRAME  -     22q11.22   [Description]    (hg38-Dec_2013)
EnsemblPRAME - 22q11.22 [CytoView hg19]  PRAME - 22q11.22 [CytoView hg38]
Mapping of homologs : NCBIPRAME [Mapview hg19]  PRAME [Mapview hg38]
OMIM606021   
Gene and transcription
Genbank (Entrez)AF025440 AI613210 AK129783 AK302188 AK304593
RefSeq transcript (Entrez)NM_001291715 NM_001291716 NM_001291717 NM_001291719 NM_001318126 NM_001318127 NM_006115 NM_206953 NM_206954 NM_206955 NM_206956
RefSeq genomic (Entrez)NC_000022 NC_018933 NG_000002 NT_011520 NT_187629 NW_004929430
Consensus coding sequences : CCDS (NCBI)PRAME
Cluster EST : UnigeneHs.30743 [ NCBI ]
CGAP (NCI)Hs.30743
Alternative Splicing GalleryENSG00000185686
Gene ExpressionPRAME [ NCBI-GEO ]   PRAME [ EBI - ARRAY_EXPRESS ]   PRAME [ SEEK ]   PRAME [ MEM ]
Gene Expression Viewer (FireBrowse)PRAME [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)23532
GTEX Portal (Tissue expression)PRAME
Protein : pattern, domain, 3D structure
UniProt/SwissProtP78395   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP78395  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP78395
Splice isoforms : SwissVarP78395
PhosPhoSitePlusP78395
Domains : Interpro (EBI)L_dom-like    PRAME_family   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)PRAME
DMDM Disease mutations23532
Blocks (Seattle)PRAME
SuperfamilyP78395
Human Protein AtlasENSG00000185686
Peptide AtlasP78395
HPRD05820
IPIIPI00019282   IPI01010791   IPI00894164   IPI00894546   IPI00894404   IPI00893742   IPI00893600   IPI00893980   
Protein Interaction databases
DIP (DOE-UCLA)P78395
IntAct (EBI)P78395
FunCoupENSG00000185686
BioGRIDPRAME
STRING (EMBL)PRAME
ZODIACPRAME
Ontologies - Pathways
QuickGOP78395
Ontology : AmiGOprotein binding  nucleus  plasma membrane  transcription, DNA-templated  apoptotic process  positive regulation of cell proliferation  cell differentiation  regulation of growth  retinoic acid receptor binding  negative regulation of apoptotic process  negative regulation of cell differentiation  negative regulation of transcription, DNA-templated  negative regulation of retinoic acid receptor signaling pathway  
Ontology : EGO-EBIprotein binding  nucleus  plasma membrane  transcription, DNA-templated  apoptotic process  positive regulation of cell proliferation  cell differentiation  regulation of growth  retinoic acid receptor binding  negative regulation of apoptotic process  negative regulation of cell differentiation  negative regulation of transcription, DNA-templated  negative regulation of retinoic acid receptor signaling pathway  
NDEx NetworkPRAME
Atlas of Cancer Signalling NetworkPRAME
Wikipedia pathwaysPRAME
Orthology - Evolution
OrthoDB23532
GeneTree (enSembl)ENSG00000185686
Phylogenetic Trees/Animal Genes : TreeFamPRAME
HOVERGENP78395
HOGENOMP78395
Homologs : HomoloGenePRAME
Homology/Alignments : Family Browser (UCSC)PRAME
Gene fusions - Rearrangements
Fusion : MitelmanPRAME/ACO2 [22q11.22/22q13.2]  
Fusion : MitelmanPRAME/HDLBP [22q11.22/2q37.3]  [t(2;22)(q37;q11)]  
Fusion: TCGAPRAME 22q11.22 ACO2 22q13.2 SKCM
Fusion: TCGAPRAME 22q11.22 HDLBP 2q37.3 SKCM
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPRAME [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PRAME
dbVarPRAME
ClinVarPRAME
1000_GenomesPRAME 
Exome Variant ServerPRAME
ExAC (Exome Aggregation Consortium)PRAME (select the gene name)
Genetic variants : HAPMAP23532
Genomic Variants (DGV)PRAME [DGVbeta]
DECIPHER (Syndromes)22:22890118-22900174  ENSG00000185686
CONAN: Copy Number AnalysisPRAME 
Mutations
ICGC Data PortalPRAME 
TCGA Data PortalPRAME 
Broad Tumor PortalPRAME
OASIS PortalPRAME [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPRAME  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPRAME
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PRAME
DgiDB (Drug Gene Interaction Database)PRAME
DoCM (Curated mutations)PRAME (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PRAME (select a term)
intoGenPRAME
NCG5 (London)PRAME
Cancer3DPRAME(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606021   
Orphanet
MedgenPRAME
Genetic Testing Registry PRAME
NextProtP78395 [Medical]
TSGene23532
GENETestsPRAME
Huge Navigator PRAME [HugePedia]
snp3D : Map Gene to Disease23532
BioCentury BCIQPRAME
ClinGenPRAME
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD23532
Chemical/Pharm GKB GenePA33698
Clinical trialPRAME
Miscellaneous
canSAR (ICR)PRAME (select the gene name)
Probes
Litterature
PubMed73 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePRAME
EVEXPRAME
GoPubMedPRAME
iHOPPRAME
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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