The origins of diffuse low-grade gliomas (DLGGs): "functional theory" versus "molecular theory"

Abstract

The improved understanding of the natural course of DLGGs 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 implies to better understand the origin of DLGG. First, because its growth rate is constant during the initial presymptomatic period, it was possible to extrapolate backward in time, leading to approximate the glioma date of birth in early adulthood. Another way to improve our knowledge about the mechanisms of DLGG genesis is to study their spatial distribution. Indeed, this tumor has preferential cerebral locations, especially in the supplementary motor area or the insular lobe - while occipital DLGG is very rare. On the basis of strong relationships between DLGG development and the eloquence of brain regions frequently invaded by this tumor, we propose a functional theory to explain the origin of DLGG. In addition, anatomo-molecular studies showed significant correlations between the DLGG locations and tumor genetics, especially with a lower rate of 1p19q codeletion in the insula. Here, the ultrastructural mechanisms of such molecular theory based on a cortical origin of DLGG will be reviewed. Finally, future directions such as potential interactions between environment-brain function-tumoral genes, the study of genetic susceptibility variants in DLGGs and the possible role of hormones in their etiology will be discussed. These crucial issues illustrate very well the close relationships between the pathophysiology of gliomagenesis, the anatomo-functional organization of the brain, and the personalized management in DLGG patients.