Liquid Biopsies for Detecting Somatic Mutations in Sporadic Cerebral Arteriovenous Malformations.

Overview

Cerebral arteriovenous malformations (CAVMs) are abnormal vessels located on the surface of the brain or within the cerebral parenchyma, causing abnormal communication between the arterial and venous networks, without the interposition of the capillary bed. The main risk associated with these malformations is rupture, which causes intracranial bleeding and can lead to serious sequelae or even death. CAVMs (except those of clearly identified genetic origin \[\< 5%\], such as mutations associated with Rendu-Osler disease) have long been considered to be of non-genetic origin. However, somatic genetic mutations that activate the RAS/RAF/MEK/ERK (MAPK) signalling pathway have recently been identified in surgical specimens of cAVMs. Furthermore, targeted inhibition of this pathway is effective in treating these malformations in animals and appears to be effective in extracranial arteriovenous malformations, particularly superficial ones.

Next-generation sequencing of circulating DNA in liquid biopsies is a promising new and minimally invasive approach for studying the presence of mutations in arteriovenous malformations. The goal of treating a cAVM is to obliterate the malformation in order to prevent or avoid the risk of haemorrhage. Several therapeutic modalities may be used, which can be combined: microsurgery, endovascular embolisation, and/or radiosurgery. However, these are invasive treatments that are not without risk. The detection of mutations by liquid biopsies would enable the development of targeted, non-invasive drug therapies against these cAVMs. The population consists of patients aged 18 years or older with cAVMs, for whom treatment by venous embolisation was recommended during a multidisciplinary consultation meeting. This research focuses on identifying somatic genetic mutations that activate the RAS/RAF/MEK/ERK (MAPK) signalling pathway in cAVMs. These mutations have already been identified in surgical specimens. This research aims to evaluate the genetic mutations identified by liquid biopsies on the drainage vein of cAVMs and the prevalence of each mutation. These liquid biopsies will be performed during embolisation surgery by sampling the drainage vein of the malformation and peripheral venous blood (no additional procedures compared to usual care).