Early childhood tumours are thought to arise from transformed embryonic cells, which often carry large copy number variants (CNVs). However, it remains unclear how CNVs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ human embryonic stem cell (hESC) differentiation to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB). We show that CNVs impair the specification of hESC-derived trunk neural crest (NC) cells and their sympathoadrenal derivatives, the putative cells-of-origin of NB. Overexpression ofMYCN, whose amplification co-occurs with CNVs in NB, exacerbates the differentiation block, and enables tumourigenic cell proliferation. We find links between disrupted cell statesin vitroand tumour cells and connect these states with stepwise disruption of developmental transcription factor networks. Together, our results chart a possible route to NB and provide a mechanistic framework for the CNV-driven initiation of embryonal tumours.
