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Grant Details

Grant Number: 1R03CA287169-01 Interpret this number
Primary Investigator: Diskin, Sharon
Organization: Children'S Hosp Of Philadelphia
Project Title: Identification and Characterization of Genetic Risk Factors in Pediatric Brain Tumors
Fiscal Year: 2024


Abstract

PROJECT SUMMARY Brain tumors are the most common form of cancer in children between 0-19 years of age in the United States, and are the largest cause of cancer-related deaths. Our long term goal is to improve the outcomes of children diagnosed with brain tumors by characterizing the germline and somatic events driving tumorigenesis so that rational, evidence-based therapies can be developed. Our objective here is to perform an integrative germline- tumor analysis of the Gabriela Miller Kids First (GMKF) X01 CA267587 pediatric brain tumor cohort to identify both inherited and de novo pathogenic or likely pathogenic (P-LP) genetic variants that may be exploitable for subtyping, risk prediction, and/or therapeutic intervention. Data from the GMKF cohort will be combined with extant sequencing data from the Pediatric Brain Tumor Atlas (PBTA) to yield 3,849 germline DNA and 4,438 tumor DNA/RNA sequences. The combined cohort spans seventeen broad histologies and includes robustly- annotated patient-parent triads/dyads (n=771). Our central hypothesis is that both inherited and de novo P-LP germline variants influence the initiation and progression of pediatric brain tumors. Here, we will test our hypothesis and accomplish our objective in two specific aims: Aim 1) Identify and assess heritability of rare P-LP variants in pediatric brain tumor triads and dyads. Rare single nucleotide variants (SNVs) and insertion- deletions (INDELS) will be investigated through a well-developed computational pipeline. Pathogenicity will be assessed using our American College of Medical Genetics (ACMG)-guided approach. Triad/dyads will be studied to assess whether variants are inherited or acquired de novo. Rare variant burden testing will be performed through comparison to multiple cancer-free cohorts. Clinical and tumor-biological correlative studies and survival analyses will be undertaken. Aim 2) Perform integrative tumor-normal analyses to elucidate functional relevance of germline P-LP variants. Somatic second hits at the gene and pathway level will be assessed for the entire cohort (N=2,558). Next, using pediatric high-grade glioma (pHGG) as a model, an expanded integrative in silico evaluation of recurrent or aggregate germline events using matched tumor DNA and RNA sequencing will be performed (N=367 pHGGs). Germline copy number variants (CNVs) will be identified and heritability assessed. Tumor sequencing data will be processed through OpenPBTA somatic workflows designed to evaluate SNV, INDELS, structural variants (SVs), and mutational signatures in DNA and account for expression profiles, isoforms, fusions and other novel transcripts in RNA. Through integration of the X01 CA267587 pediatric brain tumor cohort with extant childhood cancer and structural birth defect data, we expect to advance our understanding of the genetic basis of a diverse array of pediatric brain tumors, with insights here being applicable to the genetic basis of other childhood conditions. Moreover, we will address, for the first time, whether pediatric brain tumor genetic risk factors are inherited or acquired de novo. Completion of this project will have a sustained and positive impact on the field by identifying clinically actionable genetic alterations in these important cancers.



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