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Gene Section
Review
PRAME (preferentially expressed antigen in
melanoma)
Joel Fulton, David M Heery
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7
2RD, UK (JF, DMH)
Published in Atlas Database: April 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/PRAMEID41828ch22q11.html
DOI: 10.4267/2042/54374
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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).
Abstract
Review on PRAME, with data on DNA/RNA, on
the protein encoded and where the gene is
implicated.
Identity
Transcription
Other names: CT130, MAPE, OIP-4, OIP4
HGNC (Hugo): PRAME
Location: 22q11.22
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
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).
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).
Description
Protein
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
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(12)
Note
PRAME is a leucine-rich protein of which 21.8% of
residues are leucine or isoleucine.
941
PRAME (preferentially expressed antigen in melanoma)
Fulton J, Heery DM
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
Homology
NP_006106 : Predicted 509 amino acid, 58 kDa
protein.
Sequence homology and structural predictions
suggest that PRAME is related to the leucine-rich
repeat (LRR) family of proteins such as the Tolllike receptors. The Oogenesins 1-4 also show
considerable homology to PRAME and PRAME
family members (Dade et al., 2003).
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).
Mutations
Note
Some listed in COSMIC.
Implicated in
Melanoma
Localisation
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).
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).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(12)
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
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PRAME (preferentially expressed antigen in melanoma)
Fulton J, Heery DM
cytolytic T cells, is expressed in acute leukaemia cells. Br J
Haematol. 1998 Sep;102(5):1376-9
leukemia in addition to being a target for
immunotherapy, and biomarker for the monitoring
of minimal residual disease (Abdelmalak et al.,
2014).
Matsushita M, Ikeda H, Kizaki M, Okamoto S, Ogasawara
M, Ikeda Y, Kawakami Y. Quantitative monitoring of the
PRAME gene for the detection of minimal residual disease
in leukaemia. Br J Haematol. 2001 Mar;112(4):916-26
Neuroblastoma
Note
PRAME is expressed in high-stage neuroblastoma
and associated with poor outcome (Oberthuer et al.,
2004).
Steinbach D, Viehmann S, Zintl F, Gruhn B. PRAME gene
expression in childhood acute lymphoblastic leukemia.
Cancer Genet Cytogenet. 2002 Oct 1;138(1):89-91
Boon K, Edwards JB, Siu IM, Olschner D, Eberhart CG,
Marra MA, Strausberg RL, Riggins GJ. Comparison of
medulloblastoma and normal neural transcriptomes
identifies a restricted set of activated genes. Oncogene.
2003 Oct 23;22(48):7687-94
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).
Dadé S, Callebaut I, Mermillod P, Monget P. Identification
of a new expanding family of genes characterized by
atypical LRR domains. Localization of a cluster
preferentially expressed in oocyte. FEBS Lett. 2003 Dec
18;555(3):533-8
Ovarian adenocarcinoma
Oberthuer A, Hero B, Spitz R, Berthold F, Fischer M. The
tumor-associated antigen PRAME is universally expressed
in high-stage neuroblastoma and associated with poor
outcome. Clin Cancer Res. 2004 Jul 1;10(13):4307-13
Note
PRAME was found to be a biomarker and
prognostic factor for patients with stage III serous
ovarian adenocarcinomas (Partheen et al., 2008).
Sigalotti L, Fratta E, Coral S, Tanzarella S, Danielli R,
Colizzi F, Fonsatti E, Traversari C, Altomonte M, Maio M.
Intratumor heterogeneity of cancer/testis antigens
expression in human cutaneous melanoma is methylationregulated and functionally reverted by 5-aza-2'deoxycytidine. Cancer Res. 2004 Dec 15;64(24):9167-71
Lung squamous cell carcinoma
Note
Northern blot analysis demonstrated that high
proportion of positive tumours were shown to
express PRAME (Ikeda et al., 1997).
Birtle Z, Goodstadt L, Ponting C. Duplication and positive
selection among hominin-specific PRAME genes. BMC
Genomics. 2005 Sep 13;6:120
Head and neck cancer
Epping MT, Wang L, Edel MJ, Carlée L, Hernandez M,
Bernards R. The human tumor antigen PRAME is a
dominant repressor of retinoic acid receptor signaling. Cell.
2005 Sep 23;122(6):835-47
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).
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. The gene expression signatures of
melanoma progression. Proc Natl Acad Sci U S A. 2005
Apr 26;102(17):6092-7
Neurological neoplasms
Tajeddine N, Gala JL, Louis M, Van Schoor M, Tombal B,
Gailly P. Tumor-associated antigen preferentially
expressed antigen of melanoma (PRAME) induces
caspase-independent cell death in vitro and reduces
tumorigenicity in vivo. Cancer Res. 2005 Aug
15;65(16):7348-55
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).
Figueiredo DL, Mamede RC, Proto-Siqueira R, Neder L,
Silva WA Jr, Zago MA. Expression of cancer testis
antigens in head and neck squamous cell carcinomas.
Head Neck. 2006 Jul;28(7):614-9
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Atlas Genet Cytogenet Oncol Haematol. 2014; 18(12)
This article should be referenced as such:
Fulton J, Heery DM. PRAME (preferentially expressed
antigen in melanoma). Atlas Genet Cytogenet Oncol
Haematol. 2014; 18(12):941-944.
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