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Frequency of molecular alterations affecting ras protooncogenes in human urinary tract tumors
Abstract:
Members of the ras gene family are activated as oncogenes in many different human cancers. To systematically determine the frequency at which such genes might be involved in the neoplastic process affecting a specific target tissue, urothelial cells, we surveyed a large series of urinary tract tumors for ras oncogenes by DNA transfection and by molecular genetic analysis. Harvey (Ha)-ras oncogenes were detected in 2 of 38 tumors by transfection, molecularly cloned in biologically active form, and shown to contain single base changes at codon 61 leading to substitutions of arginine and leucine, respectively, for glutamine at this position. One additional Ha-ras oncogene was identified in a bladder carcinoma by restriction polymorphisms at codon 12. In one of 21 tumors, we observed a 40-fold amplification of the Kirsten (Ki)-ras gene. No amplification of other ras genes was detected in any of the tumors analyzed. Our findings strengthen the conclusion that codons 12 and 61 are the major "hot spots" of ras oncogene activation and suggest that quantitative alterations in expression due to gene amplification may provide an alternative mechanism for ras gene activation in primary human tumors.
Insights
Ras oncogenes are frequently activated in human cancers. This study found specific ras gene mutations and amplifications in urinary tract tumors, highlighting codons 12 and 61 as key activation sites.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ras gene family members are known oncogenes implicated in various human cancers.
- Understanding ras oncogene involvement in specific cancers, like urothelial cell neoplasms, is crucial for targeted therapies.
Purpose of the Study:
- To systematically determine the frequency of ras oncogene activation in urothelial cell-derived urinary tract tumors.
- To identify specific mutations and genetic alterations within the ras gene family in these tumors.
Main Methods:
- DNA transfection assays were used to detect activated ras oncogenes.
- Molecular genetic analyses, including cloning and restriction polymorphism analysis, were performed.
- Kirsten (Ki)-ras and Harvey (Ha)-ras gene amplification was assessed.
Main Results:
- Harvey (Ha)-ras oncogenes were identified in 2 of 38 tumors, with mutations at codon 61.
- One bladder carcinoma showed a ras oncogene with a mutation at codon 12.
- A 40-fold amplification of the Kirsten (Ki)-ras gene was observed in one of 21 tumors.
Conclusions:
- Codons 12 and 61 are confirmed as major 'hot spots' for ras oncogene activation in urinary tract tumors.
- Gene amplification represents a potential alternative mechanism for ras oncogene activation in primary human tumors.
- These findings contribute to understanding the molecular basis of urinary tract cancers.