LOCALIZATION OF A CDKN2 GENE IN LINKAGE GROUP-V OF XIPHOPHORUS FISHESDEFINES IT AS A CANDIDATE FOR THE DIFF TUMOR-SUPPRESSOR

The Xiphophorus hybrid melanoma model represents one of the earliest r eported cases of generically regulated tumor susceptibility. Melanoma formation in Xiphophorus hybrids may be explained by the inheritance o f two genes: a sex-linked oncogene, Xmrk, and a putative tumor suppres sor locus, termed DIFF, located in Linkage Group V (LG V). Several gen etic mapping procedures were used to produce a new Xiphophorus LGV map with 20 loci. All markers, particularly a recently cloned Xiphophorus CDKN2 gene family member, called CDKN2X, were tested for associations of genotype with degree of macromelanophore pigment pattern modificat ion and susceptibility to melanoma formation in backcross hybrids of s even genetic types, involving 1,110 fish and three pigment patterns. H ighly significant associations of CDKN2X genotypes with such phenotypi c effects suggests that this gene is a strong candidate for the classi cally defined DIFF tumor suppressor gene. Because published results ha ve documented the involvement of the CDKN2A (P16, MTS1, and INK4A) tum or suppressor gene in human melanoma formation, the possibility of CDK N2 genes acting as tumor suppressors in both man and Xiphophorus is li kely. (C) 1998 Wiiey-Liss, Inc.