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

About 30% of human tumours carry ras gene mutations(1,2). Of the three gene s in this family (composed of K-ras, N-ras and H-ras), K-ras is the most fr equently mutated member in human tumours, including adenocarcinomas of the pancreas (similar to 70-90% incidence), colon (similar to 50%) and lung (si milar to 25-50%)(1-6). To constuct mouse tumour models involving K-ras, we used a new gene targeting procedure to create mouse strains carrying oncoge nic alleles of K-ras that can be activated only on a spontaneous recombinat ion event in the whole animal. Here we show that mice carrying these mutati ons were highly predisposed to a range of tumour types, predominantly early onset lung cancer. This model was further characterized by examining the e ffects of germline mutations in the tumour suppressor gene p53, which is kn own to be mutated along with K-ras in human tumours. This approach has seve ral advantages over traditional transgenic strategies, including that it mo re closely recapitulates spontaneous oncogene activation as seen in human c ancers.