Abstract 144: Sex bias in neuroblastoma: Worse outcomes for female patients are associated with dysregulation of DLK1 and H19

Abstract

Abstract Neuroblastoma (NB) is a devastating neural crest-derived tumor primarily affects children under five. Forty percent of NB patients are classified as high-risk (HR), and less than half of them survive. HR disease is split into two equally sized groups: one exhibiting genetic amplification of the MYCN proto-oncogene (MA), and another where MYCN is non-amplified (MNon). Overall survival (OS) studies are often either poorly annotated or focused on outcomes across the entire patient group, which may mask differential outcomes or biases among NB subgroups. Here we report our assessment of OS among several genetic, histopathological, and sex-based subgroups in three different well annotated NB patient datasets. Our analysis reveals a previously unseen sex-bias in HR MNon patients, where female patients have significantly worse OS than males. This disparity carries into stage 4s NB, defined by high survival in infants despite the presence of broadly disseminated disease. In stage 4s patients across two studies, we observe no deaths among males (n=66) and 6 among females (n=48), again marking significantly worse OS in females. Expression analysis comparing male and female HR MNon patients identifies DLK1 and H19, two imprinted genes implicated in multiple malignancies, as frequently overexpressed in females. A similar pattern is seen in RNA seq analysis of human MA (n=4) and MNon (n=4) cell lines. In addition, both DLK1 and H19 are associated with worse prognosis in female but not male patients. We also report that depletion of either gene results in reduced growth in vitro. Moreover, the NB-related ATRX tumor suppressor has been shown to inhibit H19 via insertion of histone variant H3.3. We observe an inverse correlation between H3.3B and H19 expression in female HR MNon patients. Further, H19 levels increase upon ATRX depletion in human NB cells, suggesting that ATRX indeed regulates H19 in NB. These findings provide the first evidence of female-biased outcomes in NB and suggest functional involvement of DLK1, H19 and ATRX. Citation Format: Mariya Raleigh, Vishwa Patel, Lorraine R. Benhamou, Xin Shen, Dennis A. Sheeter, Erika C. Espinosa, Niharika Reddy Badi, Chase Calvert, Garrett Bourne, John T. Powers. Sex bias in neuroblastoma: Worse outcomes for female patients are associated with dysregulation of DLK1 and H19 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 144.