The Origins of Diffuse Low-Grade Gliomas

Abstract

The improved understanding of the natural course of diffuse low-grade gliomas (DLGG) has allowed a paradigmatic shift in their management, from a “wait-and-see” attitude to an early, individualized and dynamic therapeutic strategy. However, optimization of this management requires a better understanding the origins of DLGG. To date, the origins and etiologic factors of DLGG are mostly unknown. Beyond some data, yet limited, regarding the temporal and the cellular origins of DLGG, the mechanisms and risk factors involved in DLGG are poorly known. A way to better understand the mechanisms involved in the genesis of DLGG is to study their spatial distribution, both within the brain and at the geographical level. Indeed, some hypotheses regarding the mechanisms involved may be speculated from these distributions. It is interesting to note that DLGG have preferential locations within the brain, mostly within the so-called “functional areas”. On the basis of strong relationships between DLGG development and the eloquence of brain regions frequently invaded by these tumors, we propose a “functional theory” to explain the origin of DLGG. In addition, it can be hypothesized that the biological pathways involved in the genesis of DLGG may differ according to the tumor location, as anatomo-molecular studies showed significant correlations between the DLGG locations and tumor genetics, with a higher rate of IDH mutation and 1p19q codeletion in frontal tumors. The cellular and molecular mechanisms of such “molecular theory” will be reviewed in the present chapter. It is also interesting to note that the geographical distribution of diffuse WHO grade II and grade III gliomas is heterogeneous at the international and national levels, suggesting possible environmental risk factors. We will thus also discuss this “environmental theory". Finally, we will briefly summarize the current knowledge on genetic susceptibility in gliomas. All of these crucial issues very well illustrate the close relationships between the pathophysiology of gliomagenesis, the anatomo-functional organization of the brain, and personalized management of DLGG patients.