A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations [ATAC-seq]

Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ female human embryonic stem cell (hESC) differentiation and single-cell transcriptome and epigenome analysis to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB). We show that CNAs impair the specification of trunk neural crest (NC) cells and their sympathoadrenal derivatives, the putative cells-of-origin of NB. This effect is exacerbated upon overexpression of MYCN, whose amplification co-occurs with CNAs in NB. Moreover, CNAs potentiate the pro-tumourigenic effects of MYCN and mutant NC cells resemble NB cells in tumours. These changes correlate with a stepwise aberration of developmental transcription factor networks. Together, our results sketch a mechanistic framework for the CNA-driven initiation of embryonal tumours. 51 ATAC-seq datasets from hESCs differntiation toward trunk neural crest and sympathoadrenal derivatives at 5 key stages (day 0, 3, 9, 14, 19) and in four different experimental conditions (wt, 17q gain, 17q+1q gain, 17q+1q gain and MYCN overexpression); most sample groups are represented by 3 replicates (independent differentiation experiments with the same cell lines)