Transplacental induction of a specific mutation in fetal Ha‐ras and its critical role in post‐natal carcinogenesis

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Abstract
Mouse skin tumors were produced after transpiacental initiation [with 7, 12‐dimethylbenz(a)anthracene], only when the skin was treated post‐natally with a tumor‐promoting agent (12‐O‐tetradecanoyl phorbol 13‐acetate). DNA analysis of tumors showed that all carcinomas analyzed contained a specific mutation (A to T trans version) at the 61st codon of c‐Ha‐ras. Fifty per cent of the papillomas analyzed also had this same mutation. The A to T trans version at the 61st codon of Ha ras was heterozygous in all positive papillomas and carcinomas No such mutation was found when benzo(a) pyrene was used as an initiating agent. These results indicate that fetal c‐Ha‐ras can be trans placentally activated through a specific point mutation by a carcinogen, but a cell harboring such a mutation may remain dormant until it encounters a tumor promoting stimulus.