Activating mutations and/or expression levels of tyrosine kinase receptors GRB7, RAS, and BRAF in testicular germ cell tumors.
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.
McIntyre
Alan
A
Molecular Cytogenetics, Section of Molecular Carcinogenesis, The Institute of Cancer Research, Sutton, Surrey, UK.
Summersgill
Brenda
B
Spendlove
Hayley E
HE
Huddart
Robert
R
Houlston
Richard
R
Shipley
Janet
J
D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D051382:GRB7 Adaptor Protein / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D018239:Seminoma / Q000235:genetics* / Q000473:pathology; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology; D018631:ras Proteins
D004273:DNA, Neoplasm; D051382:GRB7 Adaptor Protein; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D019009:Proto-Oncogene Proteins c-kit; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C495955:GRB7 protein, human; C117307:KRAS protein, human; C482119:BRAF protein, human