Genetic basis for the development of adult gliomas

Abstract

Recent large-scale genome analyses have led to the discovery of several novel key genes in gliomas such as IDH1/2, CIC and ATRX. Mutations of these newly identified genes appear to play a very critical role in the development of various subtypes of adult gliomas, by working in collaboration with other genes that have been discovered over the last few decades. The latest additions are the TERT promoter mutations. They occur at one of the two hotspots within the promoter region of TERT, the reverse-transcriptase subunit of telomerase, and upregu-late TERT expression. The current understanding of the order of events is as follows: both astrocytomas and oligodendrogliomas (WHO grade II - in) develop through the acquisition of IDH mutations, possibly from common precursor cells. When TP53 and ATRX mutations subsequently occur they may become astrocytomas. When 1p19q loss is present, TERT promoter mutations and CIC mutations occur; this may lead to oligodendrogliomas. Glioblastomas mostly develop without IDH mutations and rarely have 1p19q loss. Instead they harbor simultaneous inactivation of the RB1 and p53 pathways, mostly by means of CDKN2A homozygous deletions, as well as alterations of the MAPK and/or PI3K pathways, typically by EGFR amplification and/or PTEN mutations, and TERT promoter mutations in addition. These subtype-specific genetic changes make it possible to molecularly sub-classify adult gliomas using a combination of only a few genes. Although this has conventionally been done with IDH mutations and 1p19q loss, it is now suggested that the TERT promoter status may have an additional, if not superior, role for this purpose. A future outcome-based prospective study will help establish a robust molecular diagnostic system for gliomas that incorporates objectivity and precision.