CSIG-06. BRAF GERMLINE MUTATIONS AND PREDISPOSITION TO BRAIN TUMORS

Abstract We report on two BRAF-mutated children and discuss genetic counseling regarding predisposition to brain tumors. Molecular analysis of the PTPN11 gene and twelve other genes in the RAS-MAPK pathway was carried out in a series of 54 dysmorphic patients with suspected Rasopathies. Two heterozygous BRAF germline mutations were detected in two 7-year-old girls, at exon 6 and 12 respectively. Both patients had the distinctive facial appearance of cardio-facio-cutaneous syndrome (CFC) type 1. Patients with CFC are rare and characterized by phenotypic and genetic heterogeneity, with overlaps with Noonan syndrome. While nearly 75% of CFC cases have germline BRAF mutations, the frequency of BRAF mutations is inferior in Noonan and LEOPARD syndromes. BRAF mutations in CFC are often found in the cysteine-rich domain of the BRAF protein (exons 6, 11, 12, 13, 14, 15 and 16). Conversely, somatic BRAF mutations are more common, grouped into classes according to their kinase activity level, and have been associated with a variety of malignancies, including pediatric and adult brain tumors (low- and high-grade gliomas, glioblastomas and low-grade astrocytomas). BRAF V600E is the most common somatic mutation, but other mutations are currently being identified. Many of these mutations are within the kinase domain, while others are located across the gene and have less well-understood functional consequences. Germinal V600E mutation has been described once, in a CFC patient having a severe phenotype. Nevertheless, it seems that patients with germline BRAF mutations and gliomas have not yet been reported. Given the rarity of CFC, it is unclear whether there is a high risk of brain tumors. Further molecular studies will enable us to refine recommendations for the prevention, monitoring and care of people with germline BRAF mutations, given the success of BRAF inhibitors in certain cancers, with encouraging results in gliomas.