Abstract 2506: De novo variants associated with neuroblastoma and congenital heart defects: evidence of pleiotropic effect from 1311 WGS trios
Authors: Renwick Alexander , Yu Yao , Huff Chad , Lupo Philip J. 
Published: June 2022

Abstract
Introduction: Neuroblastoma (NBL) is the most common type of extracranial pediatric solid tumor. NBL exhibits a wide spectrum of phenotypes, from low-risk cases that spontaneously regress to high-risk cases with 50% mortality, and it is responsible for 12% to 15% of deaths due to childhood cancer. While genome-wide association studies have identified a handful of risk loci, the germline genetic origins of sporadic NBL remain largely unknown. Notably, NBL is one of several childhood cancers that tend to co-occur with specific birth defects, which could point to novel genetic origins. For example, the risk of neuroblastoma is increased 3- to 7-fold among children with certain congenital heart defects (CHD). It is hypothesized that this co-occurrence arises from pleiotropic defects in the neural crest cells that are progenitors of both NBL and some heart structures. Based on these lines of evidence, we hypothesize that novel germline risk loci for NBL can be identified through pleiotropic analyses of CHD and NBL cohorts. Therefore, in this study we seek to identify germline risk loci for neuroblastoma by jointly analyzing CHD and NBL data sets with a primary focus on de novo variants.
Methods: Using whole genome sequencing data from the Gabriella Miller Kids First Data Resource Center, we will identify NBL and CHD associated loci by testing for high rates of de novo variants (DNV) in each cohort separately and in the two cohorts combined. The testing strategy compares the rate of DNV to the expected locus-specific mutation rate. In our primary analyses, we will focus on genes known to be associated with CHD in order to reduce the multiple testing penalty for that family of loci. A broader analysis will explore coding and regulatory loci genome wide to identify loci associated jointly with NBL and CHD.
Results: We acquired whole genome sequencing data of parent-offspring trios for NBL (n=609) and CHD (n=711) from the Gabriella Miller Kids First Data Resource Center. The probands in the NBL cohort was 54% male and 81% Non-Hispanic White, with a median age at diagnosis of 16 months. The probands in the CHD cohort was 59% male and 60% Non-Hispanic White. The most common CHD phenotypes were ventricular septal defect (46%), tetralogy of Fallot (32%), hypoplastic left heart syndrome (28%), atrial septal defect (25%), and right aortic arch (25%). Analyses to identify DNV are ongoing.
Conclusion: The identification of germline risk loci associated with NBL will help to inform the developmental origins of this important childhood cancer and may inform novel risk stratification protocols and therapies. This study also aims to help explain the NBL-CHD co-occurrence, and that could shed light on the development of other neural crest cell derived cancers.
Citation Format: Alexander Renwick, Yao Yu, Chad Huff, Philip J. Lupo. De novo variants associated with neuroblastoma and congenital heart defects: evidence of pleiotropic effect from 1311 WGS trios [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2506.