mycn (v myc myelocytomatosis viral related oncogene...

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Atlas Genet Cytogenet Oncol Haematol. 2012; 16(7) 488

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

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 Other names: bHLHe37, N-myc, MODED, ODED

HGNC (Hugo): MYCN

Location: 2p24.3

Local order: Centromeric to DDX1.

DNA/RNA 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).

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).

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.

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,

small cell lung carcinoma, astrocytoma; level of amplification related to the tumor progression; transgenic mice that overexpress MYCN in neuroectodermal cells develop neuroblastoma.

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 MYC-related 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



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 TH-MYCN 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).

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 SHH-driven 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).

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).

Wilms tumor Note Wilms tumor may occasionally show amplification of the MYCN protooncogene (Schaub et al., 2007). MYCN amplification is consistently associated with

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.

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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

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 Med. 1985 Oct 31;313(18):1111-6

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with small-cell lung cancer. J Natl Cancer Inst Monogr. 1992;(13):39-43

Driman D, Thorner PS, Greenberg ML, Chilton-MacNeill S, Squire J. MYCN gene amplification in rhabdomyosarcoma. Cancer. 1994 Apr 15;73(8):2231-7

Tonini GP, Boni L, Pession A, Rogers D, Iolascon A, Basso G, Cordero di Montezemolo L, Casale F, Pession A, Perri P, Mazzocco K, Scaruffi P, Lo Cunsolo C, Marchese N, Milanaccio C, Conte M, Bruzzi P, De Bernardi B. MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children. J Clin Oncol. 1997 Jan;15(1):85-93

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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.

mycn (v myc myelocytomatosis viral related oncogene...

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