Enhancer hijacking on the MYCN amplicon in neuroblastoma

MYCN amplification drives one in six neuroblastomas. In addition to harboring the MYCN oncogene, amplicons are characterized by complex structural rearrangements and co-amplify non-coding elements of the genome. The functional relevance thereof, however, is incompletely understood. Inspecting copy number data of 240 neuroblastomas, we observed an asymmetric distribution of MYCN amplicon boundaries. We showed that this pattern can be explained by a selective pressure to co-amplify a key MYCN-driving enhancer in 90 % of cases, much more recurrently than expected by chance. Subsequent epigenomic analysis indicated that this and other enhancers remain functional after amplification. Intriguingly, amplicons lacking the key local enhancer frequently incorporate distal parts of the genome. Sequencing-based amplicon reconstruction revealed that local enhancer loss can be compensated by distal enhancers juxtaposed to MYCN. As Hi-C analysis showed, these cases of enhancer hijacking arise through novel topologically associated domains. Taken together, we demonstrated how non-coding elements shape intra- and extrachromosomal MYCN amplicon structures in neuroblastoma.

Publication History

Article published online:
13 May 2020