Abstract 3811: Rare variants at 16p11.2 and within TP53 influence neuroblastoma susceptibility.
Authors: Diskin Sharon J. , Capasso Mario , Diamond Maura , Bosse Kristopher , Hakonarson Hakon , Devoto Marcella , Maris John M. 
Published: August 2014

Abstract
Background: Neuroblastoma is a cancer of the sympathetic nervous system that most commonly affects young children and accounts for approximately 10% of all pediatric oncology deaths. We have reported common single nucleotide polymorphisms (SNPs) associated with neuroblastoma within LINC00340 (NEJM 2008), BARD1 (Nat Genet, 2009), LMO1 (Nature, 2010), DUSP12 and HSD17B12 (PLoS Genet, 2011), HACE1 and LIN28B (Nat Genet, 2012), and one common CNV at 1q21.1 within NBPF23 (Nature, 2009). Collectively, however, these variants still account for less than 10% of the risk for developing neuroblastoma. Based on this observation, along with the relative paucity of somatic mutations identified in this childhood cancer, we hypothesized that rare germline variants/mutations play a significant role in tumorigenesis.
Methods and Results: We have taken a two-pronged approach to study both rare copy number variants (CNVs) and SNPs in neuroblastoma. First, we analyzed rare (&lt; 1%) CNVs in a discovery cohort of 2,083 cases and 6,146 controls and identified several large (&gt;500 Kb) CNVs associated with neuroblastoma, including a deletion at 16p11.2 (cases 0.43%, controls 0.04%; P = 4.0x10−4; OR: 8.9, 95% CI: 2.2-41.3). To date, we have replicated the 16p11.2 association in 1,167 neuroblastoma cases and 56,752 published controls (P=0.003; OR: 7.8, 95% CI: 2.3-23.6). In addition, we have validated by quantitative PCR several rare focal deletions of key developmentally regulated transcription factors, such as TBX2, detected in neuroblastoma patients but absent in 6,146 controls. In parallel, to identify relatively rare SNPs (0.5-5.0% minor allele frequency) influencing neuroblastoma susceptibility, we imputed genotypes using 1000 Genomes data in a discovery cohort of 2,101 neuroblastoma cases and 4,202 controls of European ancestry. We observed a strong association at rs78378222 (P = 6.4x10−9; OR: 2.1, 95% CI: 1.6-2.1) and rs35850753 (P = 2.2x10−9; OR: 1.9, 95% CI: 1.5-2.4), located in the 3' and 5' UTR of TP53 respectively. Both associations replicated robustly in our Italian and African-American case-series (combined rs78378222: P = 4.22 x 10−12, OR: 3.1, 95% CI: 2.1-10.1; rs35850753: P = 3.7 x 10−14; OR: 3.2, 95% CI: 2.0-9.7). These data add neuroblastoma to the subset of malignancies influenced by rs78378222, which disrupts the polyadenylation signal of TP53 having a hypomorphic effect and imparting cancer susceptibility (Nat Genet, 2011). Taken together, we show that rare CNVs and SNPs influence neuroblastoma susceptibility and have greater effect sizes than common variants reported thus far from GWAS. Efforts are ongoing to sequence the 16p11.2 region in deletion carriers and to understand the functional significance of the TP53 variants in neuroblastoma.
Conclusions: Rare DNA variations at multiple loci have a significant influence on neuroblastoma tumorigenesis and begin to address the unexplained heritability of this cancer.
Citation Format: Sharon J. Diskin, Mario Capasso, Maura Diamond, Kristopher Bosse, Hakon Hakonarson, Marcella Devoto, John M. Maris. Rare variants at 16p11.2 and within TP53 influence neuroblastoma susceptibility. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3811. doi:10.1158/1538-7445.AM2013-3811