P53, ERBB-2 AND K-RAS GENE ALTERATIONS ARE RARE IN SPONTANEOUS AND PLUTONIUM-239-INDUCED CANINE LUNG NEOPLASIA

Inhalation of high-linear energy transfer radiation in the form of rad on progeny is a suspected cause of human lung cancer. To gain insight into the types of genetic derangement(s) caused by this type of radiat ion, lung tumors from beagle dogs exposed to (239)puO(2) and those ari sing in animals with no known carcinogen exposure were examined for ev idence of aberrations in genes known to be altered in lung tumors, Alt ered expression of the p53 tumor suppressor gene and proto-oncogene er bB-2 proteins (p185(erbB2)) was evaluated by immunohistochemical analy sis of 117 tumors representing different histological types in exposed (n = 80) and unexposed (n = 37) animals, Twenty-eight tumors were ana lyzed for K-ras proto-oncogene mutations by polymerase chain reaction amplification and direct sequencing, Fourteen percent (16/116) of all lung neoplasms showed elevated nuclear accumulation of p53 protein. Re gardless of exposure history, adenosquamous and squamous cell cancers comprised 94% of all tumors with p53 abnormalities. Eighteen percent ( 21/117) of all tumors had evidence of erbB-2 protein overexpression, K -ras mutations were not detected in codons 12, 13 or 61 of tumors from unexposed (n = 9) or plutonium-exposed dogs (n = 19). These data indi cate that p53 and K-ras gene abnormalities as a result of missense mut ation are infrequent events in spontaneous and (PuO2)-Pu-239-induced l ung neoplasia in this colony of beagle dogs. Alternative mechanisms of gene alteration may be involved in canine pulmonary carcinogenesis. ( C) 1996 by Radiation Research Society