Abstract 3218: Transcriptome characterization by RNA sequencing identifies molecular and clinical subgroups in high risk neuroblastoma

Abstract

Abstract Background/objectives: Neuroblastoma (NBL) is characterized with its heterogeneous clinical and biological behavior. Despite improvement of survival rate with multimodal chemo- and immunotherapy, high mortality and morbidity is still substantial for patients with metastatic disease. Previous DNA sequencing studies characterized the genetic basis of the disease and revealed a very low somatic mutation burden and surprisingly few recurrently somatic mutated genes comparing to adult solid tumors. In order to identify the novel molecular therapeutic target and understand the biology of the high-risk neuroblastoma, we investigated gene expression profiles of tumors from a cohort of high-risk neuroblastoma patient using RNA sequencing as an integral part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. Methods: We performed RNA sequencing in a cohort of 150 high risk patients (97 survival and 53 death) using polyA selected mRNA. Gene and transcript isoform expression was used to correlate to the clinical parameters for this clinically well-annotated patient cohort. Whole exome sequencing (WES) data was available for 106 of the 150 patients cohort for combined analysis of DNA and RNA sequencing to identify expressed mutation. Results: On average, we found 12.5% of the human genome, which include 63.7% of exon, 18.0% of intron, and 4.6% of intergenic regions covered by RNA-seq reads in NB samples. Preliminary gene expression analysis showed four molecular subgroups of NB tumors with distinct outcomes (log-ranked p = 0.002). Sixty-two percent of somatic mutations identified by WES was present (>10% VAF) in the RNA transcriptome when the locus was expressed (10X). We found that some of the important pathogenic somatic mutations such as TP53 p.R243W can be only detectable by integrated analysis of the sequencing data of RNA and DNA, possibly due to low tumor purity. Future directions: We will assess the expressed mutations, fusion genes, mRNA expression, and splicing profiles to provide clinically relevant classification and offer insight into the tumor biology especially for those without detectable oncogenic driver mutation by DNA sequencing. Citation Format: Shile Zhang, Jun S. Wei, Rajesh Patidar, Young K. Song, Sivasish Sindiri, Xinyu Wen, Shahab Asgharzadeh, Robert C. Seeger, John M. Maris, Jamie M. Guidry Auvil, Daniela S. Gerhard, Javed Khan. Transcriptome characterization by RNA sequencing identifies molecular and clinical subgroups in high risk neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3218. doi:10.1158/1538-7445.AM2015-3218