Keratoacanthomas are benign skin tumors that grow rapidly but eventually regress. They occur most commonly in sun-exposed skin and are histologically remarkably similar to squamous cancers. Since mutations of the p53 tumor suppressor gene are found frequently in cutaneous squamous cell carcinomas, we hypothesized that p53 mutations might contribute to the development of keratoacanthomas. To address this question, we did p53 immunohistochemistry with a polyclonal rabbit antiserum, CM-1, that binds both mutant and wild-type p53 proteins. Although wild-type p53 protein degrades rapidly and is generally undetected by immunohistochemistry, mutant p53 protein has a longer half-life and accumulates to detectable levels. We tested 26 formalin-fixed keratoacanthomas and 4 normal skin biopsies. Positive nuclear staining was detected in 20 of 26 (77%) of the keratoacanthomas and in none of the normal skin samples. Nuclear staining occurred in the outermost layer of the neoplasms and not in the keratin-filled central cores. Since nuclear p53 protein within a cutaneous squamous cell carcinoma usually correlates with missense mutation, these data suggest that p53 mutations contribute to the development of this benign neoplasm. The histologic similarity to squamous cell carcinoma and the accumulation of p53 protein suggest progression toward malignancy, but the invariable regression of these tumors suggests an arrest at some point in multistage carcinogenesis. If this model is correct, then genetic analysis of keratoacanthomas may provide clues to the later stages of squamous carcinogenesis including local invasion and metastasis.

Angiosarcomas of the liver are rare, malignant cancers composed of neoplastic blood vessels. Human hapatic angiosarcomas have been associated with liver cirrhosis or exposure to vinyl chloride, Thorotrast or arsenic. A recent analysis of six hepatic angiosarcomas associated with vinal chloride exposure found three mutations and all were A:T --> T:A transversions, which are otherwise uncommon in human cancers. To test the specificity of this mutation spectrum, we analyzed 21 hepatic angiosarcomas not associated with vinyl chloride exposure. Four cases were exposed to Thorotrast, none had a history of arsenic exposure and the rest were sporadic. Exons 5-8 of the p53 gene were amplified by polymerase chain reaction, and the products were sequenced directly. Two G:C --> A:T transitions were found in two tumors: TGCstop in codon 136. Neither mutation was associated with Thorotrast exposure. These data indicate that p53 mutations are uncommon in sporadic hepatic angiosarcomas (2/21, 9%), and the mutational profile is consistent with endogenous mechanisms. Both features support the evidence linking vinyl chloride exposure to hepatic angiosarcomas containing an increased frequency of p53 mutations with a mutational spectrum (i.e. A:T --> T:A transversions) characteristic of chloroethylene oxide, a carcinogenic metabolite of vinyl chloride.

Tobacco smoke contains many carcinogens and has been linked with the development of lung cancer. We sequenced the conserved regions of the p53 tumour suppressor gene in lung cancers from 17 non-smokers from Hiroshima, Japan; 9 were atomic-bomb survivors. The mutations were predominantly transitions (all G:C to A:T); there were no G:C to T:A transversions. By contrast, lung cancers from 77 Japanese smokers have a predominance of G:C to T:A transversions in which the guanine residues occur on the non-transcribed DNA strand. These findings further implicate tobacco smoke carcinogens in the molecular pathogenesis of lung cancer.