Hypermutability of UV-treated plasmids in dysplastic nevus/familial melanoma cell lines.
Members of cutaneous melanoma (CM) families with dysplastic nevi (DN) are at high risk of developing CM. Using a shuttle vector plasmid, pSP189, cell lines from three patients with CM plus DN were previously found to have elevated post-UV plasmid mutability. To investigate familial occurrence of this cellular phenotype, we examined post-UV plasmid mutability in 31 lymphoblastoid cell lines from 6 familial CM kindreds. In comparison to 16 normal control lines, we found an abnormally elevated post-UV plasmid mutability in cell lines from 13 of 13 patients with CM plus DN (P = 1.5 x 10(-8)) and from 5 of 8 patients with DN only (P = 0.001). Elevated spontaneous plasmid mutation frequency (MF) was also present in cell lines from six of the CM plus DN patients (P = 0.002) and three of the DN-only patients (P = 0.028). However, cell lines from two patients with CM without DN had normal post-UV plasmid MF. Although not specific for CM patients, of 27 cell lines with elevated post-UV plasmid MF, only 8 were from donors who did not have CM + DN or DN (19 of 24 versus 8 of 28; P = 0.0003). This study indicates that post-UV plasmid hypermutability is a laboratory marker for members of melanoma-prone families and suggests that patients with familial CM have a defective mechanism for handling UV-induced DNA damage.
Moriwaki
S I
SI
Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892, USA.
Tarone
R E
RE
Tucker
M A
MA
Goldstein
A M
AM
Kraemer
K H
KH
D000367:Age Factors; D002461:Cell Line, Transformed; D004260:DNA Repair; D004416:Dysplastic Nevus Syndrome / Q000235:genetics*; D005190:Family; D005822:Genetic Vectors; D004854:Herpesvirus 4, Human; D006801:Humans; D008214:Lymphocytes; D008545:Melanoma / Q000235:genetics*; D016296:Mutagenesis; D009152:Mutagenicity Tests; D010957:Plasmids / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics