Download Gene Section MYCN (v myc myelocytomatosis viral related

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MYCN (v-myc myelocytomatosis viral related
oncogene, neuroblastoma derived (avian))
Tiangang Zhuang, Mayumi Higashi, Venkatadri Kolla, Garrett M Brodeur
Children's Hospital of Philadelphia, Oncology Research, CTRB Rm 3018, 3501 Civic Center Blvd,
Philadelphia, PA 19104, USA (TZ, MH, VK, GMB)
Published in Atlas Database: February 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/NMYC112.html
DOI: 10.4267/2042/47421
This article is an update of :
Huret JL. MYCN (myc myelocytomatosis viral related oncogene, neuroblastoma derived). Atlas Genet Cytogenet Oncol Haematol
1998;2(2):41-42.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
DNA/RNA
Other names: bHLHe37, N-myc, MODED, ODED
HGNC (Hugo): MYCN
Location: 2p24.3
Local order: Centromeric to DDX1.
Description
3 exons.
Fluorescence in-situ hybridization of MYCN probe to metaphase and interphase nuclei of a primary neuroblastoma with MYCN
amplification (Courtesy Garrett M. Brodeur, Children's Hospital of Philadelphia).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
488
MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian))
Zhuang T, et al.
MYCN (2p24). Fluorescence in-situ hybridization of MYCN probe to metaphase spread (Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics).
small cell lung carcinoma, astrocytoma; level of
amplification related to the
tumor progression; transgenic mice that overexpress
MYCN
in
neuroectodermal
cells
develop
neuroblastoma.
Protein
Description
464 amino acids; contains a phosphorylation site, an
acidic domain, an HLH motif, and a leucine zipper in
C-term; forms heterodimers with MAX and binds to an
E-box DNA recognition sequence. The consensus
sequence for the E-box element is CANNTG, with a
palindromic canonical sequence of CACGTG.
Implicated in
Neuroblastoma
Note
Neuroblastoma karyotypes frequently reveal the
cytogenetic hallmarks of gene amplification, namely
DMs or HSRs. Schwab (Schwab et al., 1983) and Kohl
(Kohl et al., 1983) originally identified the MYCrelated oncogene MYCN as the target of this
amplification event.
MYCN is located on the distal short arm of
chromosome 2 (2p24), but in cells with MYCN
amplification, the extra copies reside within these DMs
or HSRs (Schwab et al., 1984).
Additional genes may be coamplified with MYCN in a
subset of cases (DDX1, NAG, ALK), but MYCN is the
only gene that is consistently amplified from this locus.
The magnitude of MYCN amplification varies, but it
averages 100-200 copies per cell (range 5-500+
copies).The overall prevalence of MYCN amplification
is 18-20%. Amplification of MYCN is associated with
advanced stages of disease, unfavorable biological
features, and a poor outcome (Brodeur et al., 1984;
Seeger et al., 1985), but it is also associated with poor
outcome in otherwise favorable patient groups (such as
infants, and patients with lower stages of disease),
underscoring its biological importance (Seeger et al.,
1985; Look et al., 1991; Tonini et al., 1997;
Katzenstein et al., 1998; Bagatell et al., 2005; George
et al., 2005; Schneiderman et al., 2008). Therefore, the
Expression
MYCN is expressed in brain, eye, heart, kidney, lung,
muscle, ovary, placenta and thymus.
It is also expressed highly in several tumors: glioma,
lung tumor, primitive neuroectodermal tumor,
retinoblastoma (EST Profile).
Localisation
Nuclear.
Function
Probable transcription factor; possible role during
tissue differentiation.
Homology
With members of the myc family of helix-loop-helix
transcription factors.
Mutations
Somatic
Amplification, either in extrachromosomal double
minutes (DMs) or in homogeneously staining regions
within chromosomes (there is amplification when, for
example, 10 to 1000 copies of a gene are present in a
cell); found amplified in a variety of human tumors, in
particular in neuroblastoma and also in retinoblastoma,
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
489
MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian))
status of the MYCN gene is routinely determined from
neuroblastoma samples obtained at diagnosis to assist
in therapy planning (Look et al., 1991; Schwab et al.,
2004).
Indeed, because of the dramatic degree of MYCN
amplification and consequent overexpression in a
subset of aggressive neuroblastomas, it should be an
attractive therapeutic target (Pession and Tonelli, 2005;
Bell et al., 2010).
Weiss and colleagues (Weiss et al., 1997) created a
transgenic mouse model of neuroblastoma, with
MYCN expression driven in adrenergic cells by the
tyrosine hydroxylase promoter (TH-MYCN mouse).
Genomic changes in neuroblastomas arising in THMYCN mice closely parallel the genomic changes
found characteristically in human tumors (Hackett et
al., 2003). Thus, the TH-MYCN mouse model appears
to be a tractable model to study neuroblastoma
development, progression and therapy (Chessler and
Weiss, 2011).
overexpression, at least at the mRNA level. Initially,
MYCN amplification was associated almost
exclusively with the unfavorable, anaplastic subset of
Wilms tumors. However, Williams and colleagues
(Williams et al., 2011) found focal gain of MYCN in a
substantial number of both anaplastic and favorable
histologies in a survey of over 400 tumors, suggesting
that other genomic changes may account for
differences in clinical behavior.
Other tumors (retinoblastoma, small cell
lung cancer, glioblastoma multiforme)
Note
About 3-5% of primary retinoblastomas have MYCN
amplification, whereas it is much more common (27%)
in established retinoblastoma cell lines (Bowles et al.,
2007; Kim et al., 2008). MYCN is amplified in 15-25%
of small cell lung cancers, and it may be more common
in tumors at relapse (Johnson et al., 1987; Johnson et
al., 1992). MYCN amplification rarely occurs in other
lung cancer histologies (Yokota et al., 1988). MYCN
amplification occurs in a substantial number of
glioblastoma multiformes (Hui et al., 2001; Hodgson et
al., 2008), but it is rarely found in lower grade gliomas
and astrocytomas.
Medulloblastoma
Note
MYCN
amplification
is
less
common
in
medulloblastoma, a neural brain tumor of childhood,
but it is also associated with a worse clinical outcome
(Pfister et al., 2009). However, recent evidence
suggests that MYCN overexpression is much more
common in medulloblastomas, compared to normal
cerebellum (Swartling et al., 2010), and it may drive
the initiation or progression of medulloblastomas
independent of the sonic hedgehog (SHH) pathway.
Indeed, MYCN amplification is found in both SHHdriven and non-SHH-driven medulloblastomas, but
each subtype is associated with other genetic features,
suggesting they represent genetically distinct subtypes
with different prognoses (Korshunov et al., 2011).
References
Kohl NE, Kanda N, Schreck RR, Bruns G, Latt SA, Gilbert F,
Alt FW. Transposition and amplification of oncogene-related
sequences in human neuroblastomas. Cell. 1983 Dec;35(2 Pt
1):359-67
Schwab M, Alitalo K, Klempnauer KH, Varmus HE, Bishop JM,
Gilbert F, Brodeur G, Goldstein M, Trent J. Amplified DNA with
limited homology to myc cellular oncogene is shared by human
neuroblastoma cell lines and a neuroblastoma tumour. Nature.
1983 Sep 15-21;305(5931):245-8
Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM.
Amplification of N-myc in untreated human neuroblastomas
correlates with advanced disease stage. Science. 1984 Jun
8;224(4653):1121-4
Rhabdomyosarcoma (RMS)
Note
MYCN amplification also occurs in a subset of RMS,
the most common pediatric soft tissue sarcoma,
although it tends to be at a lower level (4-20 fold) than
is found in neuroblastomas. Amplification is found
predominantly in the alveolar subsest of RMS, and it is
rarely found in the more common form, called
embryonal RMS (Driman et al., 1994). However,
MYCN expression is found in the vast majority of
RMS tumors, regardless of histology, at least in
primary tumors (Toffolatti et al., 2002). For this reason,
Morgenstern and Anderson have suggested that it
would be an attractive therapeutic target for this disease
(Morgenstern and Anderson, 2006).
Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong
KY, Hammond D. Association of multiple copies of the N-myc
oncogene with rapid progression of neuroblastomas. N Engl J
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Wilms tumor
Note
Wilms tumor may occasionally show amplification of
the MYCN protooncogene (Schaub et al., 2007).
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significance of age, MYCN oncogene amplification, tumor cell
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This article should be referenced as such:
Zhuang T, Higashi M, Kolla V, Brodeur GM. MYCN (v-myc
myelocytomatosis viral related oncogene, neuroblastoma
derived (avian)). Atlas Genet Cytogenet Oncol Haematol.
2012; 16(7):488-491.
Bowles E, Corson TW, Bayani J, Squire JA, Wong N, Lai PB,
Gallie BL. Profiling genomic copy number changes in
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7)
491