Activating mutations and/or expression levels of tyrosine kinase receptors GRB7, RAS, and BRAF in testicular germ cell tumors

Neoplasia. 2005 Dec;7(12):1047-52. doi: 10.1593/neo.05514.


Amplification and/or overexpression of genes encoding tyrosine kinase receptors KIT and ERBB2 have been reported in testicular germ cell tumors (TGCTs). These receptors can bind the adaptor molecule GRB7 encoded by a gene adjacent to ERBB2 at 17q12, a region also frequently gained in TGCTs. GRB7 binding may be involved in the activation of RAS signaling and KRAS2 maps to 12p, which is constitutively gained in TGCT and lies within a minimum overlapping region of amplification at 12p11.2-12.1, a region we have previously defined. RAS proteins activate BRAF, and activating mutations of genes encoding these proteins have been described in various tumors. Here we determine the relationships between expression levels and activating mutations of these genes in a series of 65 primary TGCTs and 4 TCGT cell lines. High levels of expression and activating mutations in RAS were mutually exclusive events, and activating mutations in RAS were only identified in the seminoma subtype. Mutations in BRAF were not identified. Increased ERBB2 expression was associated with differentiated nonseminoma histology excised from lymph nodes postchemotherapy. Mutation, elevated expression, and correlations between expression levels of KRAS2, GRB7, and KIT are consistent with their involvement in the development of TGCTs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Mutational Analysis
  • DNA, Neoplasm / analysis
  • GRB7 Adaptor Protein / genetics*
  • Humans
  • Male
  • Mutation / genetics*
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Receptor, ErbB-2 / genetics
  • Seminoma / genetics*
  • Seminoma / pathology
  • Testicular Neoplasms / genetics*
  • Testicular Neoplasms / pathology
  • ras Proteins


  • DNA, Neoplasm
  • GRB7 protein, human
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • GRB7 Adaptor Protein
  • Proto-Oncogene Proteins c-kit
  • Receptor, ErbB-2
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins