2p24.3

MODED,N-myc,NMYC,ODED,bHLHe37

Neuroblastoma

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

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)

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

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)

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.