Oncogenes in human testicular cancer: DNA and RNA studies

Abstract

Oncogene dosage and expression were studied in 16 testicular neoplasms, 14 of germ cell and two of non-germ cell origin. In comparison with normal DNA, tumour DNA of a total of eight patients (seven with germ cell neoplasm and one with testicular lymphoma) showed increased dosages of KRAS2, PDGFA, EGFR, MET and PDGFB. The most frequent (occurring in six tumours) and prominent (up to 3-4-fold) increases were detected in the dosages of KRAS2 (on chromosome 12p) and PDGFA (chromosome 7p), relative to a reference locus from chromosome 2. Importantly, there was a similar increase in 12p dosage in general in these tumours, suggesting the presence of the characteristic isochromosome 12p marker. On the contrary, possible 7p polysomy (assessed by molecular methods) did not explain the PDGFA (or EGFR) changes in all cases. NRAS, MYCN, CSFIR, MYB, MYC, ABL, HRASI, TP53, and ERBB2 did not reveal any consistent alterations in tumour DNA. In RNA dot blot assays the expression of KRAS2, PDGFA, EGFR, or MYC was generally not increased in the tumour samples when compared to that in normal testicular tissue of the same patients although there was interindividual variation in mRNA levels. It thus appears that while oncogene dosage changes occur in a proportion of testis cancers, they are often part of changes in large chromosomal regions or whole arms and are seldom accompanied by altered expression. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Molecular Genetic Parameters in Pathogenesis and Prognosis of Testicular Germ Cell Tumors

“…In the testicular cell line TERA–2, the increased c–myc protein product p62 was correlated with an increased degree of cell differentiation. Similar results could be demonstrated in clinical studies of p62 protein expression demonstrating increased nuclear and cytoplasmic staining in seminomas and differentiating structures of nonseminomas, whereas undifferentiated areas of nonseminomas exhibited little activity of the protein product [55, 56]. Based on the results of these studies, aberrant expression or mutations of the relevant proto–oncogenes might result in blocking differentiation of GCTs and the tumors develop as undifferentiated histologic subtypes such as seminomas and embryonal carcinomas.…”

Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung

“…Southern blot analysis The Southern blot method was used to investigate possible amplification of the KRAS2 gene (probe p640, provided by R Weinberg) in (Peltomaki et al, 1991;Monni et al, 1996).…”

Molecular mechanisms of testicular carcinogenesis

“…Amplification of the DNA sequences of other protooncogenes, including PDGF (platelet-derived growth factor) A and B, as well as that of EGFR (epidermal growth-factor receptor) has been reported in testicular cancer samples [27]. However, analysis of the corresponding RNA has failed to identify enhanced expression of these genes, suggesting that the augmented amount of DNA is related to generalized aneuploidy in testicular tumors and not to specific alteration in these gene sequences.…”

“…Overexpression of the c-myc protein has been reported in seminomas and in the differentiated cell types in teratomas [33]. However, other investigators have been unsuccessful in identifying DNA alterations in the c-myc gene or in the genes for n-myc, c-myb, c-abl, and n-ras [27].…”

“…Although this chromosomal arm contained the sequences for the protooncogene K-ras, molecular investigations have generally failed to detect activating mutations in this gene in testicular tumors [27]. Alterations such as point mutations or gene amplification in the K-ras sequence have been reported in testicular cancer cell lines and in up to 40% of seminomas [18,44].…”