Abstract PR04: Novel somatic and germline mutations in intracranial germ cell tumors

Abstract

Abstract Intracranial germ cell tumors (IGCTs) are rare and biologically diversified tumors affecting mainly male adolescents with the highest incidence in Japan and other Asian countries2. They are divided into two main groups, pure germinoma and nongerminomatous GCTs (NGGCTs). About 10% of germinomas and most NGGCTs remain refractory to multimodality therapy. Little is currently known about IGCTs except for KIT mutation/overexpression, which is observed in ∼25% of pure germinomas and is rarely seen in NGGCTs. As yet, there are no clues for the puzzle of onset during puberty, geographic and gender discrepancy in incidence of IGCTs. Here we report the analysis of 62 cases by whole-exome sequencing, deep-targeted sequencing and SNP array. The KIT/RAS pathway was frequently mutated in pure germinomas and mixed GCTs with germinoma components. In contrast, NGGCTs appear to have a paucity of clinically actionable mutations. We identified novel recurrent somatic mutations in KIT and 8 additional genes in KIT/RAS pathway that have not been previously associated with IGCTs: downstream mediators of KIT including KRAS, NRAS, MTOR, AKT1 and its negative regulator CBL (11%). We showed frequent focal amplification at AKT1 locus (19%), leading to AKT1 overexpression. Moreover, we identified loss-of-function mutations in BCORL1 (10%), a transcriptional corepressor and tumor suppressor. Furthermore, we report for the first time, significant enrichment of novel and rare germline variants in JMJD1C, a histone demethylase and coactivator of the androgen receptor, among Japanese IGCT patients. Our data suggested a strong association of JMJD1C variants and the risk of developing of IGCTs (odds ratio=3.57). This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potential promising targets for development of novel therapeutics. This abstract is also presented as Poster A14. Citation Format: Linghua Wang, Shigeru Yamaguchi, Keita Terashima, Mathew D. Burstein, Hideo Nakamura, Tomonari Susuki, Ryo Nishikawa, Atsushi Natsume, Shunsuke Terasaka, Ho Keung Ng, Adekunle Adesina, Richard Gibbs, David Wheeler, Ching Lau. Novel somatic and germline mutations in intracranial germ cell tumors. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr PR04.