The genetic landscape of anaplastic astrocytoma

Patrick J Killela,Henry Friedman,Sian Jones,Darell D Bigner,Yiping He,Christopher J Pirozzi,Allan H Friedman,Eric Lipp,Hai Yan,Zachary J Reitman,Roger E Mclendon,B Ahmed Rasheed

doi:10.18632/oncotarget.1505

Abstract

Anaplastic astrocytoma WHO grade III (A3) is a lethal brain tumor that often occurs in middle aged patients. Clinically, it is challenging to distinguish A3 from glioblastoma multiforme (GBM) WHO grade IV. To reveal the genetic landscape of this tumor type, we sequenced the exome of a cohort of A3s (n=16). For comparison and to illuminate the genomic landscape of other glioma subtypes, we also included in our study diffuse astrocytoma WHO grade II (A2, n=7), oligoastrocytoma WHO grade II (OA2, n=2), anaplastic oligoastrocytoma WHO grade III (OA3, n=4), and GBM (n=28). Exome sequencing of A3s identified frequent mutations in IDH1 (75%, 12/16), ATRX (63%, 10/16), and TP53 (82%, 13/16). In contrast, the majority of GBMs (75%, 21/28) did not contain IDH1 or ATRX mutations, and displayed a distinct spectrum of mutations. Finally, our study also identified novel genes that were not previously linked to this tumor type. In particular, we found mutations in Notch pathway genes (NOTCH1, NOTCH2, NOTCH4, NOTCH2NL), including a recurrent NOTCH1-A465Tmutation, in 31% (5/16) of A3s. This study suggests genetic signatures will be useful for the classification of gliomas.

Highlights

Gliomas are the most common primary tumor of the central nervous system and are classified from Grade I to Grade IV on the basis of histopathological and clinical criteria established by the World Health Organization (WHO) [1, 2]
It is often very difficult to distinguish a glioblastoma multiforme (GBM) from a contrastenhancing A3 lesion by magnetic resonance imaging or histopathology alone. In addition to these purely astrocytic tumors, there are Grade II and Grade III oligoastrocytomas which present with histocytological appearances of oligodendrogliomas and astrocytomas, which can progress to GBMs
In an effort to establish the genetic landscape of progressive astrocytomas, we have sequenced the exome of a total of 57 gliomas, 30 of which were progressive astrocytomas or oligoastrocytomas (A2, n=7; A3, n=16; OA2, n = 2; OA3, n = 4; secondary GBM, n=1) and 27 of which were primary GBMs

Summary

INTRODUCTION

Gliomas are the most common primary tumor of the central nervous system and are classified from Grade I to Grade IV on the basis of histopathological and clinical criteria established by the World Health Organization (WHO) [1, 2]. The fatal nature of GBMs together with the availability of only a few minimally efficacious FDA approved treatment modalities led to the ambitious undertaking of sequencing the GBM genome in the hopes of finding unique genetic alterations to help classify tumors and identify potential therapeutic targets [48] While this pursuit has proved fruitful in identifying www.impactjournals.com/oncotarget several key genes involved in GBM tumorigenesis, relatively little has been done for the genome wide sequencing of progressive astrocytomas, including A2s, A3s, and secondary GBMs. In an effort to establish the genetic landscape of progressive astrocytomas, we have sequenced the exome of a total of 57 gliomas, 30 of which were progressive astrocytomas or oligoastrocytomas (A2, n=7; A3, n=16; OA2, n = 2; OA3, n = 4; secondary GBM, n=1) and 27 of which were primary GBMs. Our study revealed that mutations in IDH1, ATRX, and TP53 are the most frequent genetic alterations in progressive astrocytomas. Our data further supports that on a genetic level, primary GBMs displayed distinct mutation spectrums differing from those of progressive astrocytomas

RESULTS

A III OA II

METHODS

Methods for Cancer Genome Analysis