title: Novel somatic and germline mutations in intracranial germ cell tumours.
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.
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Linghua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: 1] 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.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Burstein
authors.affiliation: 1] 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.
authors.forename: Keita
authors.initials: K
authors.lastname: Terashima
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Chang
authors.affiliation: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Ho-Keung
authors.initials: HK
authors.lastname: Ng
authors.affiliation: Department of Neurosurgery, Kumamoto University, Kumamoto, 860-0862, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Zongxiao
authors.initials: Z
authors.lastname: He
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Harshavardhan
authors.initials: H
authors.lastname: Doddapaneni
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Lora
authors.initials: L
authors.lastname: Lewis
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Saitama Medical University, Saitama, 350-0495, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Neurosurgery, Saitama Medical University, Saitama, 350-0495, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
authors.affiliation: Department of Neurosurgery, Nagoya University, Nagoya, 466-8550, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Natsume
authors.affiliation: Department of Neurosurgery, Hokkaido University, Hokkaido Prefecture, 060-0808, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Terasaka
authors.affiliation: Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Dauser
authors.affiliation: Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: William
authors.initials: W
authors.lastname: Whitehead
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Adesina
authors.initials: A
authors.lastname: Adekunle
authors.affiliation: Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, Maryland 02467, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, Maryland 02467, USA.
authors.forename: Gábor
authors.initials: G
authors.lastname: Marth
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: 1] 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.
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007564:Japan; D008297:Male; D009154:Mutation / Q000235:genetics*; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins