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Somatic activation of the K-ras oncogene causes early onset lung cancer in mice


About 30% of human tumours carry ras gene mutations1,2. Of the three genes in this family (composed of K-ras, N-ras and H-ras), K-ras is the most frequently mutated member in human tumours, including adenocarcinomas of the pancreas (70–90% incidence), colon (50%) and lung (25–50%)1,2,3,4,5,6. To constuct mouse tumour models involving K-ras, we used a new gene targeting procedure to create mouse strains carrying oncogenic alleles of K-ras that can be activated only on a spontaneous recombination event in the whole animal. Here we show that mice carrying these mutations were highly predisposed to a range of tumour types, predominantly early onset lung cancer. This model was further characterized by examining the effects of germline mutations in the tumour suppressor gene p53, which is known to be mutated along with K-ras in human tumours. This approach has several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers.

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Figure 1: K-ras alleles.
Figure 2: Effect of K-rasLA mutations on survival and tumour incidence.
Figure 3: Tumour pathology in K-rasLAmutant mice.
Figure 4: Evidence of recombination in K-rasLA tumours.
Figure 5: Cooperation between K-rasLA and p53 mutations.

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We thank D. Jones, J. Whitsett, A. Mukherjee and G. Singh for advice and reagents. We also thank all laboratory members that provided input and advice on this project, as well as the Division of Comparative Medicine at MIT for their advice and care for the mice. This work was supported in part by grants from NCI, the Searle Scholars Program, and the MIT Charles Reed Fund.T.J. is an Associate Investigator of HHMI; D.A.T. is an HHMI Physician Postdoctoral Research Fellow.

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Correspondence to Tyler Jacks.

Supplementary information

Figure 1.

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Gene targeting strategy. Insertional integration ("hit") of the targeting vector into the K-ras locus produces 4 different latent alleles (ref 8, 10 and data not shown). Recombination ("run") occurs either intrachromosomally (shown here) or during unequal sister chromatid exchange (ref 10), generating mutant Kras (LA2 mice) or wild-type and mutant Kras (LA1).

Figure 2a.

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Figure 2b.

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Genetic background effects in K-rasLA mice. Kras LA mice on a pure 129/Sv background had slightly enhanced survival compared to F1 mice on a mixed B6/129 background (panel A). All mice developed lung cancer, however there were strain-specific differences in the incidence of thymic lymphoma and skin papillomas (panel B).

Figure 3.

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ACF in K-rasLA mice. ACF were identified macroscopically by methylene blue staining of wholemount colon (left panel). Hematoxylin and eosin staining of transverse secions demonstrate hyperplastic and branched crypts in the ACF (right panel).

Figure 4.

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The rearranged K-rasLA alleles are expressed. mRNAs prepared from ES cells, controltissues (C), or tumors were analyzed by RT-P CR using primers specific to exon and exon 3. Radiolabeled oligonucleotid eprobesthat distinguish between mutant and wt K-ras sequences demonstrate active mutant K-ras mRNA only in tumor samples.

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Johnson, L., Mercer, K., Greenbaum, D. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).

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