SPONTANEOUS MELANOMA FORMATION IN NONHYBRID XIPHOPHORUS

Melanoma in hybrids of Xiphophorus is due to the unrestricted activity of a cellular oncogene locus, Tu, encoding the growth factor receptor gene Xmrk. In nonhybrid parental fish, Tu is controlled by a tumor su ppressor gene. Thus, its restricted activity leads there only to a non malignant, species- and population-specific macromelanophore spot patt ern. Prompted by enigmatic reports on nonhybrid Xiphophorus with pigme ntation abnormalities resembling melanoma, we have studied pigmentatio n in descendants of wild-caught fish and purebred laboratory stocks de rived from wild populations. Whereas most stocks exhibiting macromelan ophore patterns never developed pigmentation abnormalities, an excepti onal situation for some nonhybrids was found. In X. variatus carrying the macromelanophore pattern ''punctatus-2'' and in X. cortezi with '' spotted caudal,'' expressivity of the pigmentation gene ranges from a few black spots to extreme melanosis and eventually to malignant melan oma. In X. maculatus with the mutant pigmentation gene striped'' carry ing in addition the micromelanophore pattern ''anal fin black'' or ''l ower comet,'' testosterone-dependent melanoma develop originating from the corresponding micromelanophore pattern. The tumors are highly mal ignant and express a melanoma-associated antigen, Overexpression of th e Xmrk oncogene appears as the underlying molecular mechanism for tumo r induction. These findings clearly demonstrate that tumors can also d evelop in purebred wild-type fish, The classical model for formation o f hereditary melanoma in Xiphophorus hybrids does not explain the deve lopment of melanoma in the absence of hybridization. However, their ex istence gives additional support to the reasoning that the Xmrk oncoge ne associated with the macromelanophore locus is potentially injurious .