• Lung Cancer
• Wnt Signalling Pathway
• Bronchioalveolar Carcinoma
• Cancer Stem Cells
• Esophageal Cancer
• Mesothelioma
• Expression Profiling
• Lung Cancer System Genetics
• KRas Pathway
• Other Cancers
• Diagnostics Development

Mutations in the Ras genes occur frequently in human cancers, and with clear tumor-type specificity. For instance, whereas Hras mutations are frequent in papillary thyroid cancer and Nras mutations in hepatocellular carcinoma and melanomas, mutations in Kras are predominant in lung, pancreatic and colon cancers. The reason for this tissue-specificity has been a long standing question in the Ras field.

Minh To and colleagues demonstrated that mice completely lacking Kras protein, but express Hras under the regulation of the Kras locus, were highly susceptible to carcinogen induced lung tumors. Molecular analysis showed that the majority of lung tumors in these mice have acquired an oncogenic mutation in the Hras that was knocked into the Kras locus, while the endogenous Hras gene remained unaffected. Mutation-specificity preferences therefore involve regulatory elements specific to each Ras gene, rather than functional properties of the encoded proteins.

Kras is expressed as two isoforms, Kras4A and Kras4B, as a result of alternative splicing. Kras4B is the dominant isoform and is thought to be the major effector of the oncogenic activity ascribed to mutant Kras. However, mice expressing only the Kras4B isoform turned out to be highly resistant to lung tumor development, suggesting that Kras4A is the major determinant of carcinogenesis. These findings can have major implications for the design of targeted therapies, and are published in the October issue of Nature Genetics.