Abstract 5378: Whole exome and RNA sequencing identify novel somatic mutations in gangliogliomas
Authors: Marie Suely K. , Oba-Shinjo Sueli M. , Lerario Antonio M. 
Published: August 2018

Abstract
Gangliogliomas (GG) are rare, well differentiated, slow growing neuroepithelial tumors, composed of neoplastic mature ganglion cells and neoplastic glial cells. GG comprises 0.4% of all CNS primary tumors, and 70% of GG cases are diagnosed in patients with long-term temporal lobe epilepsy. The molecular pathogenesis of GG is poorly understood. Few groups have described a high frequency of a hotspot BRAF p.V600E mutation. More recently, a co-occurrence of histone H3 p.K27M and BRAF p.V600E mutations was reported in a pediatric midline grade I GG. However, the rarity of these tumors poses challenges to uncovering a more comprehensive landscape of somatic alterations. In this study, we describe the somatic mutational profiles of 12 GG from the University of Sao Paulo Medical School in one of the largest GG case series reported to date. We performed paired germline and somatic whole exome sequencing (WES) and RNA-Seq in all cases: 9 males and 3 females with ages ranging from 1 to 49 years (mean 17 ± 13 years). These tumors were located in the temporal lobe (8), frontal lobe (1), occipital lobe (1), intraventricular region (1), and intramedullary region (1). We used the Nextera Exome Enrichment Kit (Illumina) to perform WES, and the TruSeq Stranded Total RNA (Illumina) to perform RNA-Seq. Sequencing was performed in the Illumina HiSeq 2000. We aligned reads from WES and RNA-Seq libraries to the reference genome (hg19) using BWA and STAR, respectively. We used freebayes to perform variant call from germline WES paired with the respective tumor library (WES or RNA-Seq). We used the vcfcompare tool from vcflib to filter out germline variants and annovar to annotate the final list of variants. We identified mutations in cancer-related genes in 6/12 GGs: hotspot BRAF p.V600E in 4/6 cases, biallelic NF1 mutations (p.Y333X/p.R2258X) co-occurring with hotspot H3F3A (p.K27M) and FGFR1 (p.N546K) mutations in a 13-yo female with intraventricular GG, and, finally, biallelic hotspot TP53 mutations (p.V173M, p.P172T) combined with a hotspot IDH1 (p.R132H) mutation in a 26-yo male with frontal GG. Interestingly, the same combination of mutations observed in one of our patients (FGFR1 p.N546K/H3F3A p.K27M) was recently described in a diffuse leptomeningeal tumor with glial and neuronal markers. In summary, we identified novel mutations in cancer-related genes in 6 GG (50% of our cohort), including cases with mutations in more than one known cancer driver gene. In one of the largest GG case series reported to date, this study expands the spectrum of somatic alterations in GGs to include mutations in genes recurrently altered in higher-grade gliomas, such as IDH1, NF1, and TP53.
Citation Format: Suely K. Marie, Sueli M. Oba-Shinjo, Antonio M. Lerario. Whole exome and RNA sequencing identify novel somatic mutations in gangliogliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5378.