A CDKN2-like polymorphism in Xiphophorus LG V is associated with UV-B-induced melanoma formation in platyfish-swordtail hybrids.
The genetic basis of spontaneous melanoma formation in spotted dorsal (Sd) Xiphophorus platyfish-swordtail hybrids has been studied for decades, and is adequately explained by a two-gene inheritance model involving a sex-linked oncogene, Xmrk, and an autosomal tumor suppressor, DIFF. The Xmrk oncogene encodes a receptor tyrosine kinase related to EGFR; the nature of the DIFF tumor suppressor gene is unknown. We analyzed the gentic basis of UV-B-induced melanoma formation in closely related, spotted side platyfish-swordtail hybrids, which carry a different sex-linked pigment pattern locus, Sp. We UV-irradiated spotted side Xiphophorus platyfish-swordtail backcross hybrids to induce melanomas at frequencies 6-fold higher than occur spontaneously in unirradiated control animals. To identify genetic determinants of melanoma susceptibility in this UV-inducible Xiphophorus model, we genotyped individual animals from control and UV-irradiated experimental regimes using allozyme and DNA restriction fragment length polymorphisms and tested for joint segregation of genetic markers with pigmentation phenotype and UV-induced melanoma formation. Joint segregation results show linkage of a CDKN2-like DNA polymorphism with UV-B-induced melanoma formation in these hybrids. The CDKN2-like polymorphism maps to Xiphophorus linkage group V and exhibits recombination fractions with ES1 and MDH2 allozyme markers consistent with previous localization of the DIFF tumor suppressor locus. Our results indicate that the CDKN2-like sequence we have cloned and mapped is a candidate for the DIFF tumor suppressor gene.
Nairn
R S
RS
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville 78957, USA.
Kazianis
S
S
McEntire
B B
BB
Della Coletta
L
L
Walter
R B
RB
Morizot
D C
DC
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D003532:Cyprinodontiformes / Q000235:genetics*; D005393:Fish Diseases; D016147:Genes, Tumor Suppressor; D006054:Goldfish; D006801:Humans; D008545:Melanoma / Q000209:etiology / Q000235:genetics / Q000662:veterinary*; D008969:Molecular Sequence Data; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics / Q000662:veterinary*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011995:Recombination, Genetic; D017386:Sequence Homology, Amino Acid; D014466:Ultraviolet Rays
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16