CSIG-17. MATURATION OF MALIGNANT BRAIN TUMORS: UNDERLYING MECHANISMS WITH A POTENTIAL THERAPEUTIC IMPACT

Abstract BACKGROUND Maturation is an enigmatic property of neurogenic tumors, including neuroblastoma and brain tumors in the unique cases. Multiple factors (TrkA-signaling, microenvironment, telomerase and epigenetics) have been linked to the tumor maturation. METHODS We analyzed four cases of pediatric CNS tumors (medulloblastoma SHH-activated; ETMR; unspecified CNS embryonal tumor (ET-CNS); thalamic high-grade glioma, HGG) having undergone a morphologically verified maturation to ganglioglioma, pleomorphic xanthoastrocytoma or diffuse low-grade glioma in parallel with 23 cases of maturating extracranial neuroblastoma. The paired tumor samples were analyzed using targeted NGS and gene expression profiling by NanoString. RESULTS The NanoString experiment revealed an identical shift of gene expression profile, all investigated tumors after maturation clustered together regardless of initial tumor type. MAPK (FDR=1.54×10-14), PI3K-AKT-mTOR (FDR=6.78×10-13) and TrkA signaling (FDR=2.72×10-11), cellular senescence (FDR=3.90×10-9) were predicted to be activated, while cell cycle control, DNA replication and repair (FDR respectively 1.53×10-14, 2.04×10-14 and 3.60×10-13) - repressed. Moreover, tumors completing the maturation similarly showed enhanced immunogenicity, mostly pronounced in MB and ETMR. Maturing cases of neurogenic tumors were enriched in genetic aberrations leading to MAPK cascade activation: mutations in BRAF (n=5), PTEN,PTPN11,HRAS or NF1, and a KCTD16::NTRK2 rearrangement (in neuroblastoma, ET-CNS and HGG, respectively). Genes encoding neurothophin receptors, epigenetic writers, erasers, and Kruppel-family transcription factors had similar dynamics of expression upon maturation in both CNS malignancies and neuroblastoma. NTRK1 expression was elevated at debut, whereas NTRK2 increased during maturation. Expression of negative epigenetic regulators HDAC2,HDAC10,DNMT3A and EZH2 similarly decreased in maturing tumors, while positive (SWI/SNF subunits) increased at the beginning of maturation and decreased upon the differentiation completion. KLF4, GLI1/3 expression significantly increased in the matured tumors. CONCLUSION Central and peripheral neurogenic tumors share common mechanisms of maturation, which include maintenance of MAPK signaling via neurotrophins and consistent changes in expression of epigenetic modifiers and KLF-like transcription factors.