Jeffery N. Howell, Mark H. GREENEt, Veronica M. Maher
2016
Abstract
Because of a possible etiologic link between mutations and carcinogenesis, we compared fibroblasts de- rived from skin biopsies of several patients with hereditary cu- taneous malignant melanoma and the dysplastic nevus syn- drome for sensitivity to the mutagenic and/or cytotoxic effect of broad-spectrum simulated sunlight and of a UV mimetic carcinogen, 4-nitroquinoline 1-oxide (4NQO). The genetic marker was resistance to 6-thioguanine; loss of colony-forming ability was the assay for cytotoxicity. All five strains tested were more sensitive than normal to the killing effect of 4NQO (slopes of survival curves were 2- to 3-fold steeper), but only one strain was hypersensitive to killing by Sun Lamp radia- tion. Two strains were tested for mutagenicity. The response of each to the mutagenic action of these agents corresponded to its response to cell killing. Both strains were hypermutable af- ter exposure to 4NQO, but only one showed a higher than nor- mal frequency of mutants induced by simulated sunlight. The finding that nonmalignant fibroblasts from patients with a he- reditary variant of malignant melanoma are abnormally sus- ceptible to carcinogen-induced mutations suggests that hyper- sensitivity to mutagens contributes to risk of melanoma in pa- tients. It also supports the somatic cell mutation hypothesis for the origin of cancer.