Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas

Acta Neuropathol. 2014;127(6):911-25. doi: 10.1007/s00401-014-1247-5. Epub 2014 Jan 23.

Abstract

Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 15 in Japan. The pathogenesis of iGCTs is largely unexplored. Although a subset of iGCTs is known to have KIT mutation, its impact on the biology and patients' survival has not been established. In this study, we investigated genes involved in the KIT signaling pathway. 65 iGCTs (30 pure germinomas, 14 teratomas, 18 mixed GCTs, 2 yolk sac tumors, 1 choriocarcinoma) were screened for mutation of KIT, KRAS, NRAS, HRAS, BRAF, PDGFRA, and IDH1 by direct sequencing. KIT expression was examined by immunohistochemistry and quantitative PCR. Chromosomal status was analyzed by array-comparative genomic hybridization (aCGH). Somatic mutations were detected only in KIT and RAS, which were frequently observed in pure germinomas (60.0 %), but rare in non-germinomatous GCTs (NGGCTs) (8.6 %). All KIT/RAS mutations were mutually exclusive. Regardless of the mutation status or mRNA expression, the KIT protein was expressed in all germinomas, while only in 54.3 % of NGGCTs. Amplification of KIT was found in one pure germinoma by aCGH. In pure germinomas, high expression of KIT mRNA was associated with the presence of KIT/RAS alterations and severe chromosomal instability. Our results indicate that alterations of the KIT signaling pathway play an important role in the development of germinomas. Pure germinomas may develop through two distinct pathogeneses: one with KIT/RAS alterations, elevated KIT mRNA expression and severe chromosomal instability, and the other through yet an unidentified mechanism without any of the above abnormalities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Child
  • Child, Preschool
  • Chromosomal Instability*
  • Female
  • Germinoma / genetics*
  • Germinoma / metabolism
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mutation*
  • Proto-Oncogene Proteins c-kit / genetics*
  • Proto-Oncogene Proteins c-kit / metabolism
  • RNA, Messenger / metabolism
  • Young Adult
  • ras Proteins / genetics*

Substances

  • RNA, Messenger
  • Proto-Oncogene Proteins c-kit
  • ras Proteins