Activation of the Ki‐ras gene in spontaneous and chemically induced lung tumors in CD‐1 mice

Abstract

As part of an evaluation of the effectiveness of using ras mutation analysis for distinguishing carcinogen-induced from spontaneous tumors, we examined the profile of ras gene point mutations in spontaneous, 7,12-dimethylbenz[a]anthracene (DMBA)-induced, and N-nitrosodiethylamine (DEN)-induced lung tumors from Crl:CD-1(ICR)BR (CD-1) mice. Although all of the lung tumors were assayed for mutations in the Ha-ras, Ki-ras, and N-ras genes (codons 12, 13, and 61), only Ki-ras mutations were found, which is consistent with other studies that have noted a strong preference for Ki-ras gene activation in mouse, rat, and human lung tumors. We found that spontaneous CD-1 mouse lung tumors had a very high frequency of Ki-ras gene activation (17 of 20 tumors; 85%), distributed among codons 12 (5 of 20), 13 (1 of 20), and 61 (11 of 20). DMBA-induced lung tumors had a slightly higher frequency of Ki-ras gene mutations (16 of 16; 100%), again distributed among codons 12 (5 of 16), 13 (2 of 16), and 61 (9 of 16). However, seven of the DMBA tumors had mutations qualitatively different from those found in spontaneous tumors. In contrast to DMBA-induced tumors, DEN-induced tumors had a lower frequency of Ki-ras mutations (36%) when compared with spontaneous lung tumors, suggesting that DEN primarily induces lung carcinogenesis by a mechanism other than ras gene activation. Thus, although spontaneous and induced CD-1 mouse lung tumors have a strong tissue-specific preference for carrying an activated Ki-ras gene, the nature of the initiating carcinogen can influence the frequency or profile of Ki-ras mutations.

Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis

“…No mutations were detected in codon 12, 13 or 61 of K-ras or N-ras genes Skin tumorigenesis in H-ras deficient mice K Ise et al However, we found that the majority of DMBAinduced tumors in H-ras(7/7) mouse skin had G?C transversion in the K-ras codon 12 or 13, which have not been reported previously in the skin tumors induced by DMBA. Mutations at guanine residues by DMBA are not unprecedented, since ras mutations detected in primary bladder epithelial cells treated with DMBA in vitro were invariably G?A transitions in Kras codon 12 (Brookes et al, 1988) and the majority of DMBA-induced liver tumors had a G?C transversion in K-ras codon 13 (Manam et al, 1992). These results show that DMBA causes guanosine adducts as well as adenosine adducts.…”

Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes

“…K-Ras is mutated to an activated form in ∼30% of NSCLCs, c-Myc is up-regulated in 20%-30%, the p53 tumor suppressor gene is mutated or deleted in ∼50%, and the Ink4A/Arf locus is often deleted or hypermethylated. K-Ras mutations are also observed in a substantial number of sporadic and chemically induced lung adenocarcinomas in mice (Manam et al 1992;Cazorla et al 1998;Tuveson and Jacks 1999).The probable precursors to lung adenocarcinomas are either type II alveolar epithelial cells or Clara cells (Malkinson 1991;Rehm et al 1991). Transgenic mouse models of lung cancer have been produced by expressing potent viral oncogenes in these cell types (Glasser et al 1994).…”

“…K-Ras is mutated to an activated form in ∼30% of NSCLCs, c-Myc is up-regulated in 20%-30%, the p53 tumor suppressor gene is mutated or deleted in ∼50%, and the Ink4A/Arf locus is often deleted or hypermethylated. K-Ras mutations are also observed in a substantial number of sporadic and chemically induced lung adenocarcinomas in mice (Manam et al 1992;Cazorla et al 1998;Tuveson and Jacks 1999).…”

Bin3 Deletion Causes Cataracts and Increased Susceptibility to Lymphoma during Aging

“…S1A and B). Similarly, in mice exposed to a single dose of DEN, a ras-activating mutagen that induces lung and liver tumors with limited penetrance (34), null mice also exhibited a greater sensitivity to the formation of lung adenocarcinoma (Supplementary Table S2; Supplementary Fig. S1C).…”