CNS germinomas show global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways

Introduction: Only limited information is available on their genomic, epigenetic and biological alterations of CNS germinomas.

Methods: A genome-wide analysis of chromosomal copy number alterations was performed in 49 CNS germinomas by molecular inversion profiling. CpG methylation was studied by immunohistochemistry of methylated cytosine residues. KIT and RAS family members were sequenced. Ras/Erk and Akt pathway activation was analyzed by immunostaining of p-Erk, p-Akt, p-mTOR and p-S6.

Results: Germinomas showed global DNA demethylation and genomic instability with high frequency of regional gains and losses including gene amplifications. Mutations of KIT and RAS gene family members indicated activation of signaling pathways. Co-activation of Ras/Erk and Akt pathways was found in 83% of germinomas.

Conclusions: Germinomas display demethylated DNA similar to primordial germ cells associated with extensive genomic instability. Mutational activations of Kit-, Ras/Erk- and Akt-pathways indicate their biological importance and their components as potential targets for therapy.