Genomic Landscape of Intramedullary Spinal Cord Gliomas

Ming Zhang,George I Jallo,Qing Wang,Joanna Wang,Tej D Azad,Fausto J Rodriguez,Rajiv R Iyer,Mari L Groves,Tomas Garzon-Muvdi,Daniel M Sciubba,Ziya Gokaslan,Jean-Paul Wolinsky,Chetan Bettegowda,Ann Liu,Charles Eberhart,Peter Burger

doi:10.1038/s41598-019-54286-9

Abstract

Intramedullary spinal cord tumors (IMSCTs) are rare neoplasms that have limited treatment options and are associated with high rates of morbidity and mortality. To better understand the genetic basis of these tumors we performed whole exome sequencing on 45 tumors and matched germline DNA, including twenty-nine spinal cord ependymomas and sixteen astrocytomas. Though recurrent somatic mutations in IMSCTs were rare, we identified NF2 mutations in 15.7% of tumors (ependymoma, N = 7; astrocytoma, N = 1), RP1 mutations in 5.9% of tumors (ependymoma, N = 3), and ESX1 mutations in 5.9% of tumors (ependymoma, N = 3). We further identified copy number amplifications in CTU1 in 25% of myxopapillary ependymomas. Given the paucity of somatic driver mutations, we further performed whole-genome sequencing of 12 tumors (ependymoma, N = 9; astrocytoma, N = 3). Overall, we observed that IMSCTs with intracranial histologic counterparts (e.g. glioblastoma) did not harbor the canonical mutations associated with their intracranial counterparts. Our findings suggest that the origin of IMSCTs may be distinct from tumors arising within other compartments of the central nervous system and provides the framework to begin more biologically based therapeutic strategies.

Highlights

Intramedullary spinal cord tumors (IMSCTs) are a heterogeneous group of rare lesions that can cause significant morbidity in both children and adults
Investigation of inheritable syndromes such as neurofibromatosis type 1 and 2 (NF1, NF2) and von-Hippel Lindau has illuminated particular genetic aberrations that can lead to IMSCT formation; these molecular mechanisms are often absent in sporadic IMSCTs, whose genetic and molecular profiles are less well understood[5,6,7,8,9]
Our results demonstrate that IMSCTs of comparable histopathology to their intracranial counterparts have distinct mutational profiles and may have different genetic origins

Summary

Introduction

Intramedullary spinal cord tumors (IMSCTs) are a heterogeneous group of rare lesions that can cause significant morbidity in both children and adults. Strategies for chemotherapeutic intervention for IMSCTs have included the application of established regimens and protocols described for other central nervous system (CNS) tumors with similar histology[10,11,12,13]. Clinically appealing, this approach may be ineffective and potentially hazardous given an increasing body of evidence that the genetic makeup and mutation spectra of histologically comparable CNS tumors can vary considerably[14,15,16,17,18]. We performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) of a diverse cohort of IMSCTs to elucidate the genetic profiles of IMSCT subtypes

Methods

Results

Conclusion