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

Novel somatic and germline mutations in intracranial germ cell tumours.

Author information

  • 1Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 2Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 31] Structural and Computational Biology and Molecular Biophysics Program, Baylor College of Medicine, Houston, Texas 77030, USA [2] Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 41] Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas 77030, USA [2] National Center for Child Health and Development, Tokyo, 157-8535, Japan.
  • 5Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
  • 6Department of Neurosurgery, Kumamoto University, Kumamoto, 860-0862, Japan.
  • 7Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 8Department of Neurosurgery, Saitama Medical University, Saitama, 350-0495, Japan.
  • 9Department of Neurosurgery, Nagoya University, Nagoya, 466-8550, Japan.
  • 10Department of Neurosurgery, Hokkaido University, Hokkaido Prefecture, 060-0808, Japan.
  • 11Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 12Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 13Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 14Department of Biology, Boston College, Chestnut Hill, Maryland 02467, USA.
  • 151] Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas 77030, USA [2] Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA [3] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.

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.

PMID:
24896186
[PubMed - indexed for MEDLINE]
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