Abstract 4756: Exome sequencing of 81 neuroblastomas identifies a wide diversity of somatic mutation

TL;DR: An analysis of 162 whole exome sequences from 81 tumor/normal pairs from high-risk NBL patients identifies genetic mutations that encode such targets and plans a concerted effort to catalogue potentially detrimental germline variations in order to further extend the understanding of the heritable component of NBL.

Abstract: Neuroblastoma (NBL) is a cancer arising from the peripheral nervous system and is the most common solid tumor outside the brain in infants and children. Despite improved treatment over the past 20 years, only 45% of those with high-risk disease survive emphasizing the need for new molecular targets for therapy. To identify genetic mutations that encode such targets, we present an analysis of 162 whole exome sequences from 81 tumor/normal pairs from high-risk NBL patients (N=27 with MYCN amplification). From each sample, genomic DNA fragments encoding 185,961 exons from 18,380 genes were isolated using in-solution hybrid capture and sequenced using the Illumina sequencing platform to a median of 195X coverage. A wide diversity of somatic variation was observed with non-silent mutation counts ranging from 5 to 149 per tumor (median=24). Novel hyper-mutation phenotypes (> 125 candidate coding somatic mutations) were observed in four tumors including one case with both a deletion and a truncating mutation in MLH1. Several genes were mutated across the set at a statistically significant level including ALK (6 tumors, q=0.006) and PTPN11 (3 tumors, q=0.012). There are 27 other genes with candidate mutation frequencies in the 4-10% range, but no single gene identified to date with a mutation frequency >10%. Importantly, multiple paired blood samples (acquired at diagnosis) have sufficient numbers of circulating tumor DNA to potentially interfere with our SNV detection algorithm; refinement of the analytic pipeline using SNP-derived “contamination” metrics is ongoing. We anticipate validating candidate somatic candidates using an orthogonal genotyping method and further defining their true frequency in an expanded sample set that includes non-high-risk cases as well. Finally, we plan a concerted effort to catalogue potentially detrimental germline variations in order to further extend our understanding of the heritable component of NBL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4756. doi:10.1158/1538-7445.AM2011-4756