KIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literature.
Testicular germ cell tumours (TGCTs) are the leading cause of cancer deaths in young male Caucasians. Identifying changes in DNA copy number can pinpoint genes involved in tumour development. We defined the smallest overlapping regions of imbalance in TGCTs using array comparative genomic hybridization analysis. Novel regions, or regions which refined those previously reported, were identified. The expression profile of genes from 12p, which is invariably gained in TGCTs, and amplicons defined at 12p11.2-12.1 and 4q12, suggest KRAS and KIT involvement in TGCT and seminoma development, respectively. Amplification of these genes was not found in intratubular germ cell neoplasia adjacent to invasive disease showing these changes, suggesting their involvement in tumour progression. Activating mutations of RAS genes (KRAS or NRAS) and overexpression of KRAS were mutually exclusive events. These, correlations between the expression levels of KIT, KRAS and GRB7 (which encodes an adapter molecule known to interact with the KIT tyrosine kinase receptor) and other reported evidence reviewed here, are consistent with a role for activation of KIT and RAS signalling in TGCT development. In order to assess a role for KIT in seminomas, we modulated the level of KIT expression in TCam-2, a seminoma cell line. The likely seminomatous origin of this cell line was supported by demonstrating KIT and OCT3/4 overexpression and gain of 12p material. Reducing the expression of KIT in TCam-2 through RNA inhibition resulted in decreased cell viability. Further understanding of KIT and RAS signalling in TGCTs may lead to novel therapeutic approaches for these tumours.
Goddard
N C
NC
Molecular Cytogenetics, Section of Molecular Carcinogenesis, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
McIntyre
A
A
Summersgill
B
B
Gilbert
D
D
Kitazawa
S
S
Shipley
J
J
D000293:Adolescent; D000328:Adult; D002869:Chromosome Aberrations; D002881:Chromosomes, Human, Pair 12; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D015398:Signal Transduction; D013736:Testicular Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D018631:ras Proteins / Q000502:physiology*
D019009:Proto-Oncogene Proteins c-kit; D018631:ras Proteins