Like the study of cytogenetic markers, the study of molecular markers is in its infancy. At present, despite extensive study of numerous proto-oncogenes, few have been implicated in testicular germ cell tumorigenesis. Two potentially responsible genes are hst-1 and c-kit. The hst-1 gene is located on the long arm of chromosome 11 and encodes fibroblast growth factor. Expression has been shown in 63% of NSGCT tissue samples but in only 4% of seminomas. In contrast, c-kit, which encodes a tyro-sine kinase growth factor receptor, is expressed predominantly in seminoma tissue (c-kit expressed in 80% seminoma vs 7% NSGCT).49 The interaction of c-kit with its natural ligand, stem cell factor (SCF), has been implicated in enhanced tumor growth. It has been suggested that the binding of SCF to cells expressing c-kit increases cell survival, and alteration of SCF expression has been seen in GCTs.50 This is of particular interest as the SCF gene is located at region 12q22, an area known to have loss of heterozygosity in over 40% of GCTs.48
The role of tumor suppressor genes in testicular cancer has not been widely studied and is a potential fertile area of future investigation. Despite the limited information available, the retinoblastoma gene (RB) and p53 have shown potential as markers for GCTs. Strohmeyer and colleagues found decreased RB ribonucleic acid in all GCTs and found no RB protein product in seminomas, embryonal carcinomas, and choriocarcinomas. RB gene mutations, however, could not be identified, suggesting a missed subtle gene micromutation or a mechanism at the level of transcription.51 Sequencing of the p53 gene in GCTs rarely reveals mutations. In a recent review, in only
6.7% of 281 tumors sequenced was a mutation found.52-54 Again, however, the gene product has been shown to be abnormal. Wild-type p53 protein product has a very short half-life and is almost undetectable by immunohistochemistry. Mutated p53 protein, in contrast, is more stable and is therefore detectable. The p53 product has been detected in 77% of GCTs, again suggesting a transcriptional or posttranscrip-tional mechanism.54 P53 has been shown to be involved in triggering apoptosis induced by DNA-damaging agents.55 The data supporting the role of p53 as a clinical chemosensitizing agent in metastatic GCT are conflicting. Baltaci and colleagues showed that p53 levels were significantly related to complete response, partial response, and treatment failure. Kersemaekers and colleagues, however, failed to show a correlation between p53 levels and treatment response.56 Both studies, unfortunately, were limited by their small population: 24 and 35 patients, respectively. P53 has also been investigated in clinical stage I disease. In 149 patients, p53 levels did not appear to predict pathologic stage II disease.57
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