Abstract 3280: Sequencing approaches define the mutation and fusion landscape of choroid plexus carcinomas
Authors: Merino Diana M. , Li Yongjin , Ma Xiaotu , Zhang Jinghui , Malkin David , Gilbertson Richard J. 
Published: August 2015

Abstract
Background & Purpose: Choroid plexus carcinomas (CPCs) are aggressive intraventricular tumors accounting for ∼20% of brain tumors in children under 2 years of age. The clinical outcome of CPC patients is variable having an average 5-year overall survival of 50%. A recent study from our group has characterized copy number, DNA methylation and gene expression aberrations in these tumors and identified that a greater number of mutated copies of TP53 is significantly associated with reduced survival. The mutational landscape of these tumors is largely unknown, although this information is crucial to refine the understanding of CPC tumorigenesis and identify novel therapeutic targets. The purpose of this study is to complement the in-depth analysis of the molecular abnormalities driving CPC development by investigating single nucleotide alterations (SNAs), and structural variations (SVs) in CPC DNA and RNA.
Methods: A cohort of 29 high quality samples from 25 pediatric CPC patients was used for this study. DNA from 4 blood-tumor pairs and RNA from 27 CPCs were used for whole genome sequencing (WGS) and RNA sequencing (RNA seq), respectively, as part of the Pediatric Cancer Genome Project (PCGP) at St. Jude Children's Research Hospital, using the Illumina Genome Analyzer IIx or HiSeq platform with 100bp read length. Eighty-two percent of samples were primary tumors, while 17.2% were recurrences. Only one sample had sufficient high quality nucleic acid material to conduct both DNA and RNA sequencing.
Results: CPCs exhibited very low levels of SNAs ranging from 1 to 11 SNAs per genome. Copy number analysis using WGS confirmed the high levels of copy number alterations in CPCs. RNAseq analysis revealed that primary and recurrent CPC samples exhibited 100% similarity in fusion breakpoints, suggesting very little clonal divergence in these pediatric brain tumors. A recurrent fusion in chromosome 3 was observed in two independent CPCs (7%). Other fusion events generated in-frame alterations in genes involved in the MAP kinase pathway, such as PPP2R1A, and in apoptosis and cell proliferation pathways. The sample for which WGS and RNAseq was generated exhibited chromothripsis with numerous SVs affecting chromosomes 1 and 19. No other SV events were found in our CPC cohort.
Conclusions: CPCs exhibit very few SNAs and SVs, but are characterized by recurrent chromosome-wide copy number aberrations. Various RNA fusion events altering the MAP kinase pathway have been identified, suggesting a key role for kinase pathways in the development and growth of these devastating brain tumors.
Citation Format: Diana M. Merino, Yongjin Li, Xiaotu Ma, Jinghui Zhang, David Malkin, Richard J. Gilbertson. Sequencing approaches define the mutation and fusion landscape of choroid plexus carcinomas. [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 3280. doi:10.1158/1538-7445.AM2015-3280