Molecular Testing of Brain Tumor

Abstract

The World Health Organization (WHO) classification of central nervous system (CNS) tumors was revised in 2016 with a basis on the integrated diagnosis of molecular genetics. We herein provide the guidelines for using molecular genetic tests in routine pathological practice for an accurate diagnosis and appropriate management. While astrocytomas and IDH-mutant (secondary) glioblastomas are characterized by the mutational status of IDH, TP53 , and ATRX , oligodendrogliomas have a 1p/19q codeletion and mutations in IDH, CIC , FUBP1 , and the promoter region of telomerase reverse transcriptase ( TERTp ). IDH-wildtype (primary) glioblastomas typically lack mutations in IDH, but are characterized by copy number variations of EGFR, PTEN, CDKN2A/B, PDGFRA , and NF1 as well as mutations of TERTp . High-grade pediatric gliomas differ from those of adult gliomas, consisting of mutations in H3F3A, ATRX , and DAXX , but not in IDH genes. In contrast, well-circumscribed low-grade neuroepithelial tumors in children, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often have mutations or activating rearrangements in the BRAF, FGFR1, and MYB genes. Other CNS tumors, such as ependymomas, neuronal and glioneuronal tumors, embryonal tumors, meningothelial, and other mesenchymal tumors have important genetic alterations, many of which are diagnostic, prognostic, and predictive markers and therapeutic targets. Therefore, the neuropathological evaluation of brain tumors is increasingly dependent on molecular genetic tests for proper classification, prediction of biological behavior and patient management. Identifying these gene abnormalities requires cost-effective and high-throughput testing, such as next-generation sequencing. Overall, this paper reviews the global guidelines and diagnostic algorithms for molecular genetic testing of brain tumors.

Keywords: Brain neoplasms; Molecular biology; Next generation sequencing; Pathological diagnosis.

Fig. 1.

Schematic view of the classification of adult diffuse glioma according to the status of key genes.

Fig. 2.

Schematic view of the classification of pediatric diffuse gliomas according to the status of key genes. LG, low grade; HG, high grade; NOS, not otherwise specified. ^aCharacteristic but not required for diagnosis.

Fig. 3.

Schematic view, photographs, and reading criteria of the FISH probes for detecting 1p and 19q deletion. The FISH probes are long enough to find out the whole arm deletion. 1p/19q deleted cases show one orange signal and two green signals. The diagnostic cut-off of 1p and 10q deletion is written in the box. FISH, fluorescent in situ hybridization; LOH, loss of heterozygosity; CGH, comparative genomic hybridization; WES, whole exome sequencing.