Novel sex-biased outcomes in neuroblastoma are associated with distinct gene expression and chromosomal loss patterns.

The worst patient outcomes in neuroblastoma are driven by high-risk disease 1,2 , which is divided into similarly sized MYCN amplified and MYCN non-amplified patient subgroups 3 . Male patients have been reported to have slightly worse outcomes than females in all-patient analyses of multiple studies 3,4 . However, we show here that in MYCN non- amplified high-risk and stage 4s low-risk disease, female patients have significantly worse overall survival than males. Female MYCN non-amplified high-risk patients highly express H19 and DLK1 , both of which drive cell growth in vitro and are associated with worse outcomes in females but not males. Further, chromosome-specific expression analysis of these patients reveals broad sex disparities in chromosomal patterning, including female-specific retention of chromosome 11q, a pattern typically reserved for MYCN -amplified disease 5,6 . Finally, we show that H19 , a known let-7 microRNA target 7 , sequesters let-7 in females, providing a rationale for worse female survival and reconciling retention of chromosome 11q. We propose that this novel sex-based outcome disparity is driven by let-7 inhibition, expanding on a model of neuroblastoma development where let-7 mitigation is central to disease pathology 8 .