A pediatric brain tumor atlas of genes deregulated by somatic genomic rearrangement

Yiqun Zhang,Lawrence A Donehower,Chad J Creighton,Michael E Scheurer,Fengju Chen

doi:10.1038/s41467-021-21081-y

Abstract

The global impact of somatic structural variants (SSVs) on gene expression in pediatric brain tumors has not been thoroughly characterised. Here, using whole-genome and RNA sequencing from 854 tumors of more than 30 different types from the Children’s Brain Tumor Tissue Consortium, we report the altered expression of hundreds of genes in association with the presence of nearby SSV breakpoints. SSV-mediated expression changes involve gene fusions, altered cis-regulation, or gene disruption. SSVs considerably extend the numbers of patients with tumors somatically altered for critical pathways, including receptor tyrosine kinases (KRAS, MET, EGFR, NF1), Rb pathway (CDK4), TERT, MYC family (MYC, MYCN, MYB), and HIPPO (NF2). Compared to initial tumors, progressive or recurrent tumors involve a distinct set of SSV-gene associations. High overall SSV burden associates with TP53 mutations, histone H3.3 gene H3F3C mutations, and the transcription of DNA damage response genes. Compared to adult cancers, pediatric brain tumors would involve a different set of genes with SSV-altered cis-regulation. Our comprehensive and pan-histology genomic analyses reveal SSVs to play a major role in shaping the transcriptome of pediatric brain tumors.

Highlights

The global impact of somatic structural variants (SSVs) on gene expression in pediatric brain tumors has not been thoroughly characterised
Our study focused on 854 pediatric brain tumor samples from the Children’s Brain Tumor Tissue Consortium (CBTTC), representing 759 patients, for which both whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) data were available (Supplementary Data 1)
Tumor samples in CBTTC spanned at least 33 different tumor types based on histology, the most highly represented of which (13 or more tumors for each) included: lowgrade glioma/astrocytoma (PLGG, n = 239 tumors), medulloblastoma (MBL, n = 104), ependymoma (EPMT, n = 79), highgrade glioma/astrocytoma (PHGG, n = 76), ganglioglioma (GNG, n = 48), craniopharyngioma (CRANIO, n = 36), atypical teratoid rhabdoid tumor (ATRT, n = 30), meningioma (MNG, n = 30), dysembryoplastic neuroepithelial tumor (DNT, n = 24), schwannoma (SCHW, n = 16), neurofibroma/plexiform (NFIB, n = 16), choroid plexus papilloma (CPP, n = 14), and supratentorial or spinal cord primitive neuroectodermal tumor (PNET, n = 13)

Summary

Introduction

The global impact of somatic structural variants (SSVs) on gene expression in pediatric brain tumors has not been thoroughly characterised. Using whole-genome and RNA sequencing from 854 tumors of more than 30 different types from the Children’s Brain Tumor Tissue Consortium, we report the altered expression of hundreds of genes in association with the presence of nearby SSV breakpoints. Pediatric brain tumors would involve a different set of genes with SSV-altered cis-regulation. Over 20 studies carried out in conjunction with the PCAWG consortium explored various aspects of noncoding genomic alteration in cancer Among these studies of the PCAWG sample cohort, we reported that hundreds of genes showed recurrently altered expression in association with the nearby presence of an SSV breakpoint[3].

Methods

Results

Conclusion