Stem cell factor receptor (c-KIT) codon 816 mutations predict development of bilateral testicular germ-cell tumors

Leendert H J Looijenga, Hubert de Leeuw, Monique van Oorschot, Ruud J H L M van Gurp, Hans Stoop, Ad J M Gillis, Carlos A de Gouveia Brazao, Rob F A Weber, Wim J Kirkels, Thamar van Dijk, Marieke von Lindern, Peter Valk, Geczy Lajos, Edit Olah, Jahn M Nesland, Sophie D Fosså, J Wolter Oosterhuis

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167 Citations (Scopus)


Testicular germ-cell tumors (TGCTs) of adolescents and adults originate from intratubular germ cell neoplasia (ITGCN), which is composed of the malignant counterparts of embryonal germ cells. ITGCN cells are characterized, among others, by the presence of stem cell factor receptor c-KIT. Once established, ITGCN will always progress to invasiveness. Approximately 2.5-5% of patients with a TGCT will develop bilateral disease and require complete castration, resulting in infertility, a need for lifelong androgen replacement, and psychological stress. To date, the only way to predict a contralateral tumor is surgical biopsy of the contralateral testis to demonstrate ITGCN. We did a retrospective study of 224 unilateral and 61 proven bilateral TGCTs (from 46 patients, in three independently collected series in Europe) for the presence of activating c-KIT codon 816 mutations. A c-KIT codon 816 mutation was found in three unilateral TGCT (1.3%), and in 57 bilateral TGCTs (93%; P < 0.0001). In the two wild-type bilateral tumors for which ITGCN was available, the preinvasive cells contained the mutation. The mutations were somatic in origin and identical in both tumors. We conclude that somatic activating codon 816 c-KIT mutations are associated with development of bilateral TGCT. Detection of c-KIT codon 816 mutations in unilateral TGCT identifies patients at risk for bilateral disease. These patients may undergo tailored treatment to prevent the development of bilateral disease, with retention of testicular hormonal function.

Original languageEnglish
Pages (from-to)7674-8
Number of pages5
JournalCancer research
Issue number22
Publication statusPublished - 15 Nov 2003
Externally publishedYes


  • Adult
  • Codon/genetics
  • DNA, Neoplasm/blood
  • Genetic Predisposition to Disease
  • Germinoma/genetics
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Polymerase Chain Reaction/methods
  • Proto-Oncogene Proteins c-kit/genetics
  • Seminoma/genetics
  • Testicular Neoplasms/genetics


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