Abstract B24: Characterization of somatically acquired regulatory mutations in high-risk neuroblastoma

Abstract

Abstract Neuroblastoma is a childhood cancer of the developing peripheral nervous system and is uniquely characterized by a broad spectrum of phenotypes ranging from spontaneous tumor regression to relentless progression. The 5-year survival rate for children in the low- and intermediate-risk groups is over 95%; however, children with high-risk disease have a 40-50% likelihood of survival despite aggressive multimodal therapy. High-risk neuroblastomas harbor relatively few protein coding mutations at diagnosis, with the oncogenic mechanisms underlying MYCN amplification and ALK activation remaining obscure. We therefore hypothesized that characterizing high-risk neuroblastoma noncoding genetic variation will define gene regulatory mechanisms driving tumor progression, and that somatically acquired noncoding mutations alter critical neurodevelopmental gene regulatory regions. Here, we have integrated neuroblastoma cell line histone ChIP-Seq (N = 10), ATAC-Seq (N = 12), and RNA-Seq (N = 39) with high-risk patient (N = 105) whole-genome mutation data to define the landscape of noncoding somatic events dysregulating enhancers and promoters in high-risk neuroblastoma. We found a significantly higher number of mutations per patient in high-risk and stage 4 patients, compared to other risk groups (Wilcox Whigh-low = 129.5, p = 1.47e-07; Whigh-int = 70, p = 3.66e-08) and stages (WStage4-Stage3 = 86, p = 2.68e-3; WStage4-Stage4s= 65.5, p = 1.21e-12). We found a median of 1,809 somatic noncoding single nucleotide mutations per patient, and a subset of these recurrently mutate sequences underlying super-enhancer peaks of 102 genes. An additional subset lie within CCCTC-binding factor (CTCF) motifs (a median of 5 mutations per patient), suggesting potential dysregulation of chromosome looping in neuroblastoma. Understanding noncoding drivers of oncogenic gene expression and translating these basic science discoveries to the clinic is a critical step towards changing the devastating course of this disease. Citation Format: Jo Lynne Harenza, Gregory Chen, John M. Maris. Characterization of somatically acquired regulatory mutations in high-risk neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B24.