Germline duplication of MYCN predisposes to childhood embryonal tumours
Menée à partir de données génomiques portant sur 113 431 personnes, cette étude analyse l'association entre des microduplications 2p incluant le locus MYCN et le risque de tumeurs embryonnaires infantiles (neuroblastome et tumeur de Wilms)
Background: Neuroblastoma and Wilms tumour (WT) are common childhood embryonal malignancies. Germline 2p24 duplication has been reported in several cases of neuroblastoma and WT, either as part of a larger 2p duplication or as a microduplication involving just 2p24.3. Although the larger duplications involve many genes, including ALK, the microduplications have been localised to a region including MYCN and DDX1.
Methods: We analysed Whole Genome Sequence data from adults and children sequenced for various indications. We utilised a workflow to extract structural and copy number variants, filtered to include duplications or gains of 2 kb–20 Mb, including these loci, followed by manual inspection in IGV. Associations were assessed using Fisher's exact test. Penetrance was estimated by Bayesian calculation of the conditional probability of disease.
Findings: Among 113,431 genomes, there were 6 participants with a microduplication that included the MYCN locus. Of these, two had a diagnosis of WT and one of neuroblastoma. The 2p24.3 microduplication was therefore identified in 3/197 with a definite history of WT/neuroblastoma and 3/113,234 without such a history (p < 0.0001). Penetrance is estimated to be 13%. Twelve participants were identified with a 2p24.3 microduplication that included the DDX1 locus but not MYCN, none of whom received a diagnosis of a childhood embryonal tumour.
Interpretation: We have shown that 2p24.3 microduplications that include MYCN predispose to childhood embryonal tumours and should be routinely assessed when WT or neuroblastoma predisposition is suspected. We have also shown that there does not appear to be any increased incidence of childhood tumours when DDX1 alone is duplicated.
eBioMedicine , article en libre accès, 2026