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B-raf and Ha-ras mutations in chemically induced mouse liver tumors
Maike Jaworski1, Albrecht Buchmann, Peter Bauer
11Institut für Pharmakologie und Toxikologie, Abteilung Toxikologie, Universität Tübingen, Wilhelmstr. 56, 72074 Tübingen, Germany.
Abstract:
The mitogen-activated protein kinase signalling pathway is a central regulator of tumor growth, which is constitutively activated in chemically induced mouse liver tumors. In about 30-50% of cases this effect can be related to activation of the Ha-ras gene by point mutations, whereas in the remaining cases mutations may occur in other members within this pathway, such as Raf kinases. Recently, B-raf has been shown to be frequently mutated in human melanomas and certain other cancers, with a V599E amino-acid change representing the most predominant mutation type. We now screened 82 N-nitrosodiethylamine-induced liver tumors from C3H/He mice for mutations within the hotspot positions in the Ha-ras and B-raf genes. About 50% (39/82) of tumors showed Ha-ras codon 61 mutations and 16 tumors ( approximately 20%) harbored mutations at codon 624 of the B-raf gene, which corresponds to codon 599 in human B-raf. None of the tumors was mutated in both Ha-ras and B-raf. The high prevalence of Ha-ras and B-raf mutations in mouse liver tumors is in striking contrast to human hepatocellular cancers which very infrequently harbor mutations in the two genes. These fundamental differences between the biology of liver tumors in mice and man may be of toxicological relevance.
Insights
Chemically induced mouse liver tumors frequently exhibit mutations in the Ha-ras and B-raf genes, key regulators of tumor growth. These genetic alterations differ significantly from those found in human liver cancers, suggesting distinct tumor biology.
Area of Science:
- Oncology
- Molecular Biology
- Toxicology
Background:
- The mitogen-activated protein kinase (MAPK) signaling pathway is crucial for tumor growth and is often overactive in liver tumors.
- Mutations in Ha-ras and Raf kinases, including B-raf, are implicated in pathway activation.
- The V599E mutation in B-raf is common in human cancers like melanoma.
Purpose of the Study:
- To investigate the frequency and types of mutations in the Ha-ras and B-raf genes in chemically induced mouse liver tumors.
- To compare the mutation profiles of mouse liver tumors with those observed in human hepatocellular cancers.
Main Methods:
- Screening of 82 N-nitrosodiethylamine-induced liver tumors from C3H/He mice.
- Analysis focused on hotspot mutation positions within the Ha-ras and B-raf genes.
Main Results:
- Approximately 50% of tumors (39/82) displayed Ha-ras codon 61 mutations.
- Around 20% of tumors (16/82) showed mutations in B-raf at codon 624 (human equivalent codon 599).
- No tumors exhibited mutations in both Ha-ras and B-raf.
Conclusions:
- Mouse liver tumors frequently harbor Ha-ras and B-raf mutations, unlike human hepatocellular cancers.
- These genetic discrepancies highlight fundamental differences in liver tumor biology between mice and humans.
- Such differences may have significant implications for toxicological studies and cancer research.
