Exomic sequencing of four rare central nervous system tumor types

Abstract

A heterogeneous population of uncommon neoplasms of the central nervous system (CNS) cause significant morbidity and mortality. To explore their genetic origins, we sequenced the exomes of 12 pleomorphic xanthoastrocytomas (PXA), 17 non-brainstem pediatric glioblastomas (PGBM), 8 intracranial ependymomas (IEP) and 8 spinal cord ependymomas (SCEP). Analysis of the mutational spectra revealed that the predominant single base pair substitution was a C:G>T:A transition in each of the four tumor types. Our data confirm the critical roles of several known driver genes within CNS neoplasms, including TP53 and ATRX in PGBM, and NF2 in SCEPs. Additionally, we show that activating BRAF mutations play a central role in both low and high grade glial tumors. Furthermore, alterations in genes coding for members of the mammalian target of rapamycin (mTOR) pathway were observed in 33% of PXA. Our study supports the hypothesis that pathologically similar tumors arising in different age groups and from different compartments may represent distinct disease processes with varied genetic composition.

Figure 1A. Pleomorphic xanthoastrocytoma (WHO grade II).

Pleomorphic xanthoastrocytoma represents a distinctive glioma subtype. Histologically it is characterized by the presence of nuclear pleomorphism (e.g. variation in nuclear size), a fascicular arrangement of cells and eosinophilic granular bodies (arrow).

Figure 1B. Pediatric glioblastoma (WHO grade IV).

Morphologic features of pediatric glioblastomas are similar to those found in adult patients. Pseudopalisading necrosis is a characteristic finding (center), and diagnostic of glioblastoma when present in a mitotically active infiltrating astrocytoma.

Figure 1C. Intracranial ependymoma (WHO grade III).

Perivascular pseudorosettes are a histologic hallmark of ependymoma, and represent neoplastic cell processes surrounding intratumoral vessels. Brisk mitotic activity is present in this intracranial ependymoma (arrows), which suffices to classify it as anaplastic.

Figure 1D. Spinal cord ependymoma (WHO grade II).

Spinal cord ependymomas are typically low grade, and demonstrate low proliferative activity. Perivascular pseudorosettes, composed of numerous perivascular glial processes (arrows), are frequent characteristic histologic features.