INCREASING MELANOMA INCIDENCE - PUTATIVELY EXPLAINABLE BY RETROTRANSPOSONS - EXPERIMENTAL CONTRIBUTIONS OF THE XIPHOPHORINE GORDON-KOSSWIG MELANOMA SYSTEM

The worldwide accelerating increase of neoplasia in humans is difficul t to explain. We use the Xiphophorus tumor model to approach this prob lem by melanoma provocation with X-rays. Melanoma develops following i nappropriate expression of x-erb B-conducted developmental genes and t heir controllers. These oncodeterminants are inherited according to Me ndelian rules. We detected a new type of oncodeterminants that, follow ing a single treatment of embryos with X-rays, generates a self-genera ting non-Mendelian melanoma transmission and accelerating increase of its incidence in succeeding generations (e.g., 0-->18-->33-->52%). To localize these oncodeterminants, we crossed nonirradiated fish having half of their chromosomes irradiated with nonirradiated fish having no ne of, half of, or all of their chromosomes irradiated. Because tumor rate and expression in the following generations correspond to the rat es of treated chromosomes, we conclude that the new oncodeterminants a re distributed over the chromosomes of the fish, where they may increa se in the changing generations. By means of xiphophorine-specific retr oviral DNA, we isolated two retrotransposons that behave hereditarily like the new transgenerational oncodeterminants. Sequence analysis rev ealed three ORFs flanked by LTRs containing motives of regulatory sequ ences typical for known retroviral and retrotransposal LTRs. Pol- and env-resembling sequences are lacking. Southern and in situ hybridizati on showed their multiple and repetitive nature distributed throughout the chromosomes and indications for their capability to increase in nu mber without further treatment. Their transcripts are expressed in con cert with those of most of the other known xiphophorine tumor determin ants. Their expression is extremely high in cell cultures from tumorou s embryos derived from ancestors treated as embryos with X-rays.