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

Abstract

AbstractThe worst patient outcomes in neuroblastoma are driven by high-risk disease1,2, which is divided into similarly sizedMYCNamplified andMYCNnon-amplified patient subgroups3. Male patients have been reported to have slightly worse outcomes than females in all-patient analyses of multiple studies3,4. However, we show here that inMYCNnon- amplified high-risk and stage 4s low-risk disease, female patients have significantly worse overall survival than males. FemaleMYCNnon-amplified high-risk patients highly expressH19andDLK1, both of which drive cell growthin vitroand 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 forMYCN-amplified disease5,6. Finally, we show thatH19, a knownlet-7microRNA target7, sequesterslet-7in 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 bylet-7inhibition, expanding on a model of neuroblastoma development wherelet-7mitigation is central to disease pathology8.