Novel somatic and germline mutations in intracranial germ cell tumours

Abstract

Intracranial germ cell tumors (IGCTs) are a group of rare heterogeneous brain tumors which are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographic and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically 5–8 fold greater in Japan and other East Asian countries than in Western countries1 with peak incidence near the time of puberty2. About half of the tumors are located in the pineal region. The male-to-female incidence ratio is approximately 3–4:1 overall but even higher for tumors located in the pineal region3. Due to the scarcity of tumor specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next generation sequencing, SNP array and expression array. We find the KIT/RAS signaling pathway frequently mutated in over 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 gain 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 corepressor and tumor suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, a histone demethylase and 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.

Pluripotency Transcription Factor Oct4 Mediates Stepwise Nucleosome Demethylation and Depletion

“…Recent work suggests that Jmjd1c associates with the transcription factor Nanog (56), but evidence for a functional role as a Nanog cofactor is lacking. Jmjd1c is important for maintenance of spermatogonial germ cells (57), and rare germ line Jmjd1c variants are associated with certain germ cell tumors (58). In addition, Jmjd1c is a downstream Oct4 target (59), suggesting a possible regulatory loop.…”

Reprogramming of germ cells into pluripotency

“…Single nucleotide polymorphisms (SNPs) of PTEN have been identified as risk factors for testicular teratomas [55] . In addition, mutations in MTOR and TRP53 and copy number gains in AKT1 are frequently observed in intracranial teratomas and yolk sac tumors [54,56] . On the other hand, variants of sprouty4, encoding a nega tive regulator for MAPK signaling, are associated with testicular teratomas [53] .…”

“…A strong association between a variant of KITLG and the occurrence of testicular teratomas has been reported. KIT mutations, which activate kinase activity in a ligand independent manner, are found frequently in testicular seminomas but not in testicular teratomas or yolk sac tumors [53,54] . CBL mutations have been found in Sekita Y et al .…”

“…KRAS and NRAS mutations, which activate both PI3K/Akt and MAPK signaling, are frequently detected in seminomas and teratomas [54] . Single nucleotide polymorphisms (SNPs) of PTEN have been identified as risk factors for testicular teratomas [55] .…”

“…CBL mutations have been found in Sekita Y et al . Germ cell reprogramming teratomas, yolk sac tumors, and mixedtype tumors composed of germinomas and nongerminomatous tumors, all of which occur intracranially [54] . Because CBL encodes ubiquitin ligase for receptor tyrosine kinases, including KIT, mutations may lead to KIT overexpression.…”