Novel somatic and germline mutations in intracranial germ cell tumours

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Abstract

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries1, with peak incidence near the time of puberty2. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3–4:1 overall, but is even higher for tumours located in the pineal region3. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations inKIT, its downstream mediatorsKRASandNRAS, and its negative regulatorCBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of theAKT1locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations inBCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants inJMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

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