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Kras regulatory elements and exon 4A determine mutation specificity in lung cancer

Nature Genetics volume 40, pages 1240–1244 (2008)Cite this article

Abstract

Kras is the most frequently mutated ras family member in lung carcinomas1,2, whereas Hras mutations are common in tumors from stratified epithelia such as the skin. Using a Hras knock-in mouse model3, we demonstrate that specificity for Kras mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target ras genes. Although the Kras 4A isoform is dispensable for mouse development4,5, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wild-type (WT) Kras on the mutant allele6,7. Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The two Kras isoforms undergo different post-translational modifications8; therefore, these findings can have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers.

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Figure 1: Ras protein levels and effects on downstream signaling effectors in Hras and Kras knock-in mice.
Figure 2: Hras knock-in mice are highly susceptible to urethane-induced lung tumors.
Figure 3: Lung tumors from Hras knock-in mice show papillary, solid and mixed growth patterns, and contain cells with an epithelioid morphology.
Figure 4: The KrasKI allele renders mice resistant to urethane-induced lung carcinogenesis and is deficient in suppression of lung tumor development in KrasLA2 animals.
Figure 5: Kras 4A is expressed in normal lung epithelium but not significantly in tumors.

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Acknowledgements

This work was supported by CA111834 and CA084244 (A.B.). M.D.T. was supported in part by a Sandler Foundation Postdoctoral Research Fellowship. C.E.W. was supported by the Swiss National Science Foundation (SNSF). R.D.L. was supported by a grant of Associazione Italiana per la ricerca sul cancro (AIRC). A.B. acknowledges support from the Bruce and Davina Isackson Foundation and from the Barbara Bass Bakar Chair of Cancer Genetics. Phospho-Akt was provided by D. Stokoe (University of California San Francisco), and primary antibodies against CCA/CC10 were a gift from A. Mukherjee (National Institute of Child Health and Human Development, US National Institutes of Health).

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Authors and Affiliations

  1. University of California San Francisco Helen Diller Family Comprehensive Cancer Center, Cancer Research Institute, San Francisco, 94115, California, USA

    Minh D To, Christine E Wong, Anthony N Karnezis, Reyno Del Rosario & Allan Balmain

  2. Department of Pathology, University of California San Francisco, San Francisco, 94115, California, USA

    Anthony N Karnezis

  3. Stazione Zoologica Anton Dohrn, Naples, 80121, Italy

    Roberto Di Lauro

  4. Institute of Genetic Research “Gaetano Salvatore” (IRGS), Biogem s.c.a.r.l., 83031, Ariano Irpino, Italy.,

    Roberto Di Lauro

Authors
  1. Minh D To
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  2. Christine E Wong
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  3. Anthony N Karnezis
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  5. Roberto Di Lauro
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  6. Allan Balmain
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Contributions

M.D.T. and A.B. designed the study. All experiments involving mice were performed by M.D.T. and R.D.R. M.D.T. performed protein analysis and mutational analysis. C.E.W. performed immunohistochemistry, and A.N.K. performed histological evaluations of lung lesions. R.D.L. provided Hras and Kras knock-in mice and was involved in interpretation of results. M.D.T. and A.B. wrote the paper, and all authors contributed to the manuscript preparation.

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Correspondence to Allan Balmain.

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Supplementary Figure 1, Supplementary Tables 1 and 2 (PDF 645 kb)

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To, M., Wong, C., Karnezis, A. et al. Kras regulatory elements and exon 4A determine mutation specificity in lung cancer. Nat Genet 40, 1240–1244 (2008). https://doi.org/10.1038/ng.211

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