MBRS-37. RECURRENT ACTIVATING MUTATIONS OF AKT GENES IN WNT-ACTIVATED MEDULLOBLASTOMAS

Medulloblastoma (MB) can be classified into four distinct molecular subgroups (WNT group, SHH group, group 3, and group 4). Medulloblastoma of the WNT subgroup (WNT-MB) are commonly associated with favorable prognosis. Prospective molecular analysis based on a combination of CGH-array, targeted NGS and Nanostring-based subgrouping on 272 MB was conducted. Our custom targeted NGS panel of 75 genes includes genes recurrently affected in MB together with actionable genes with therapeutic purpose including some involved in the PIK3/AKT signaling pathway. Among the 272 MB analyzed, 26 cases (9.6%) belonged to the WNT subgroup based on CTNNB1 mutations, monosomy of chromosome 6 and Nanostring-based molecular subgrouping. Our targeted NGS revealed three hotspot activating mutations in AKT3 in WNT-MB and only one cases in another MB subgroup (in a group 4 MB; among the 33 cases of confirmed group 4 MB in our cohort). We subsequently performed Sanger sequencing of the hotspot Glu17 codon of AKT1, AKT2, and AKT3 in 42 additional WNT-MB. This analysis revealed six additional activating mutations of AKT genes (four AKT3 and two AKT1 hotspots mutations) in WNT-MB. Altogether, we report 9/68 (13.2%) cases of WNT-MB with AKT genes mutations (two mutations in AKT1 and seven mutations in AKT3). Our molecular analysis revealed AKT hotspot mutations that presumably activate the PIK3/AKT signaling pathway in WNT-MB. Even though WNT-MB is the subgroup of MB with the most favorable prognosis, this result emphasizes a possibility of targeted therapy that need to be further explored in vitro and in vivo.