MYCN – Neuroblastoma

MYCN is amplified in approximately 20–30% of childhood neuroblastoma and serves as a robust biomarker of high-risk disease. Initial reports identified MYCN amplification in 20% of cases, correlating independently with poor prognosis in stage IV disease (PMID:9212845). Multi-cohort analyses confirmed significant enrichment of MYCN amplification in older patients (>1 year; 18/36) compared to infants, suggesting age-dependent oncogenic selection (PMID:1362216).

High-level MYCN amplification (>50-fold) has been detected in primary, lymph node, and hepatic metastases, accompanied by structural rearrangements downstream of exon 3, indicating complex locus alterations in tumor progression (PMID:2004381). Constitutional microduplication of 2p24.3 encompassing only the MYCN locus predisposes to stage 4 neuroblastoma and distinctive craniofacial and limb anomalies (global developmental delay HP:0001263, postaxial polydactyly HP:0100259, hypertelorism HP:0000316, high forehead HP:0000348) (PMID:23401364).

In adult and adolescent-onset neuroblastoma, MYCN amplification (2/7 cases) co-occurs with telomere maintenance alterations (TERT rearrangements, ATRX loss) in ~80% of cases, defining a high-risk molecular subgroup (PMID:31749253). TERT rearrangements and MYCN amplification independently drive telomerase activation and poor outcome, underscoring the mechanistic link between MYCN dosage and telomere stabilization (PMID:27793328).

Functional studies demonstrate that activated ALK (F1174L/R1275Q) upregulates MYCN transcription via RTK downstream signaling; co-expression of ALK(F1174L) and MYCN in murine neural crest progenitors accelerates tumor onset and increases lethality. Combined ALK and mTOR inhibition overcomes crizotinib resistance in ALK-mutant/MYCN-driven tumors (PMID:22789543; PMID:22286764).

Clinically, MYCN amplification is associated with reduced event-free and overall survival in stage 4 neuroblastoma and acts synergistically with the MDM2 SNP309 G allele to further worsen prognosis (stage 4 OS TG/GG vs TT: P = 0.008) (PMID:19526525; PMID:20006005).

References

• Medical and Pediatric Oncology • 1997 • Concomitant p53 mutation and MYCN amplification in neuroblastoma. PMID:9212845
• Journal of Pediatric Surgery • 1992 • Differences of L-myc polymorphic patterns of neuroblastoma in patients under 1 year versus older ages: a preliminary report. PMID:1362216
• Cancer Research • 1991 • Neuroblastoma with DNA amplification and rearrangement in the N-myc gene region. PMID:2004381
• American Journal of Medical Genetics Part A • 2013 • Neuroblastoma in a pediatric patient with a microduplication of 2p involving the MYCN locus. PMID:23401364
• Genes, Chromosomes & Cancer • 2020 • Adult-onset neuroblastoma: Report of seven cases with molecular genetic characterization. PMID:31749253
• Journal of Pediatric Surgery • 2016 • Telomere biology including TERT rearrangements in neuroblastoma: a useful indicator for surgical treatments. PMID:27793328
• Cancer Cell • 2012 • The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. PMID:22789543
• Oncogene • 2012 • Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells. PMID:22286764
• Pediatric Blood & Cancer • 2009 • MDM2 SNP309 genotype influences survival of metastatic but not of localized neuroblastoma. PMID:19526525
• Journal of Pediatric Surgery • 2009 • Risks and benefits of ending of mass screening for neuroblastoma at 6 months of age in Japan. PMID:20006005

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