PDTM-01. GERMLINE GENETIC PREDISPOSITION TO PEDIATRIC GLIOMA. (5th November 2018)

• Record Type: Journal Article
• Authors: Muskens, Ivo; Walsh, Kyle; de Smith, Adam; Morimoto, Libby; Metayer, Catherin; Ma, Xiaomei; Wiemels, Joseph
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi203
• Page End: vi203
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.843
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: INTRODUCTION: Pediatric gliomas constitute a majority of pediatric brain tumors and intermediate to high grade gliomas have high mortality. While some advances have been made over recent years with regards to pediatric glioma etiology, genetic predisposition has not been investigated thoroughly. In this study, the role of rare germline variants on risk of pediatric glioma was evaluated in 322 astrocytoma patients (predominantly grade II and III) using whole-exome sequencing and detailed evaluation of 162 known cancer-related genes. METHODS: DNA samples were extracted from neonatal dried bloodspots from 322 pediatric glioma patients born and diagnosed in California, and sequenced using the Personalis ACE whole-exome sequencing platform. Exome alignment and variant calling was performed using Samtools and GATK 3.8. SnpEff and Combined Annotation Dependent Depletion (CADD) tools were used for variant annotation. Only variants that were not present in the 1000 Genomes dataset, had allele frequency smaller than 0.01% in the Exome Aggregation Consortium (ExAC) database, a CADD score greater than 20, and a moderate or high variant effect impact were included to identify rare putatively deleterious variants. RESULTS: All samples passed quality control and the mean read depth was 41.4. Seventy-one (22.0%) samples harbored a mutation that was potentially deleterious in at least one of the 162 cancer-related genes. The most commonly affected gene encodes a specific receptor tyrosine kinase (RTK) (28 patients, 8.7%), followed by a DNA polymerase enzyme(5 patients), and a specific mismatch repair protein(5 patients). Alterations of the tyrosine kinase protein may impact cell growth, mutation, and maturation of nerve cells. CONCLUSION: This study supports a role for rare germline mutations in the etiology of pediatric glioma and implicates RTK biology in glioma predisposition. These findings have translational implications for risk prediction and targeted therapy.