Novel somatic and germline mutations in intracranial germ cell tumours

Nature. 2014 Jul 10;511(7508):241-5. doi: 10.1038/nature13296. Epub 2014 Jun 4.

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 countries, with peak incidence near the time of puberty. 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 region. 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 in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Child
  • Female
  • Germ-Line Mutation / genetics*
  • Humans
  • Japan
  • Male
  • Mutation / genetics*
  • Neoplasms, Germ Cell and Embryonal / genetics*
  • Neoplasms, Germ Cell and Embryonal / pathology
  • Oncogene Protein v-akt / genetics
  • Proto-Oncogene Proteins c-kit / genetics
  • Reproducibility of Results
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics
  • Young Adult
  • ras Proteins / genetics

Substances

  • Proto-Oncogene Proteins c-kit
  • Oncogene Protein v-akt
  • TOR Serine-Threonine Kinases
  • ras Proteins