# Germline duplication of MYCN predisposes to childhood embryonal tumours

## TL;DR

A genetic duplication in the MYCN gene increases the risk of childhood embryonal tumors like neuroblastoma and Wilms tumor.

## Contribution

The study identifies germline duplication of the MYCN locus as a novel predisposing factor for childhood embryonal tumors.

## Key findings

- 2p24.3 microduplications including MYCN were found in 3 individuals with childhood embryonal tumors and 3 without.
- Penetrance of the MYCN duplication for these tumors is estimated at 13%.
- DDX1 duplication alone does not appear to increase the risk of childhood embryonal tumors.

## Abstract

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.

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.

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.

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.

UCL Great Ormond Street Institute of Child Health Child Health Research CIO PhD Studentship, 10.13039/501100002203Brain Tumour Charity, 10.13039/501100001273Children with Cancer UK, 10.13039/501100001279Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, 10.13039/501100000289Cancer Research UK and the 10.13039/501100000272National Institute for Health Research.