Abstract LB-355: Whole-exome sequencing of intracranial germ cell tumors reveals frequent mutations in KIT and RAS pathways and histone demethylases.

Abstract

Abstract Intracranial germ cell tumors (IGCTs) are a group of rare pediatric brain tumors affecting mainly male adolescents and young adults. The incidence of IGCTs varies significantly according to geographic locations with the highest incidence in Japan and other East Asian countries. Taken together, these characteristics suggest predisposing germline factors. IGCTs can be divided into two main groups, pure germinoma and nongerminomatous germ cell tumor (NGGCT). The former in general responds well to chemoradiotherapy whereas the latter has a rather poor prognosis. Currently the only known gene associated with this disease is KIT, which is mutated in ~25% of IGCTs. Due to the scarcity of tissues available for research, the molecular biology of IGCTs remains largely unknown. Thus, deeper understanding of the pathogenesis of these unusual tumors should lead to new insights into the underlying cancer biology and the development of novel therapeutics for this rare and deadly disease. Using whole-exome sequencing and SNP array, we have analyzed 28 IGCT tumors (12 pure germinomas, 12 NGGCTs and 4 mixed GCTs) collected from Japan (21), Hong Kong (4) and United States (3). Somatic mutations of KIT were detected in 29% of cases, primarily in germinomas. In an additional 38% of the cases, deleterious somatic mutations were identified in important downstream mediators of KIT signal transduction including KRAS, NRAS, MTOR and their respective regulators, NF1 and PTEN. Mutations in KIT were mutually exclusive with mutations in RAS. Furthermore, 21% of patients showed inactivation of tumor suppressor genes (TSGs) including BCORL1, PTEN, NF1 and SMAD3. Inactivation of TSGs coexisted in tumors with activation of KIT/RAS oncogenes, suggesting these mutations act cooperatively in tumorigenesis. Copy-number analysis revealed almost exclusively arm-level gains and losses. Over 90% of the germinomas exhibited chromosomal imbalance and uniparental disomy of multiple chromosomes, suggesting aberrant meiotic division may possibly play a role in the pathogenesis of this disease. Patterns of chromosome imbalance within a given tumor revealed subclonal structure in 58% of the analyzed cases. Finally, we found in this cohort a significant enrichment (39%) of novel or rare germline variants in histone demethylases, compared with the control cohorts, suggesting epigenetic deregulation may be an important early event in tumorigenesis. One histone demethylase harbored a risk allele present at significantly higher frequency in our male cases compared to a Japanese control population, a finding that could explain both the population prevalence and sex differences in this disease. This study has important implications for our understanding of the pathogenesis of IGCTs, and suggests potential targets for the development of therapeutics focused on inhibitors of KIT/RAS activation. Citation Format: Linghua Wang, Shigeru Yamaguchi, Keita Terashima, Matthew D. Burstein, Jiayi M. Sun, Tomonari Suzuki, Ryo Nishikawa, Hideo Nakamura, Atsushi Natsume, Shunsuke Terasaka, Ho-Keung Ng, Robert C. Dauser, William E. Whitehead, Adesina M. Adekunle, Donna M. Muzny, Richard A. Gibbs, Ching C. Lau, David A. Wheeler. Whole-exome sequencing of intracranial germ cell tumors reveals frequent mutations in KIT and RAS pathways and histone demethylases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-355. doi:10.1158/1538-7445.AM2013-LB-355