Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN . MYCN is itself a target of let-7 , a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B , an inhibitor of let -7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN . Here we show, however, that LIN28B is dispensable in MYCN -amplified neuroblastoma cell lines, despite de-repression of let-7 . We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7 , which reconciles the dispensability of LIN28B . We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B , MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.