Nonmammalian Models for Sunlight Carcinogenesis: Genetic Analysis of Melanoma Formation in Xiphophorus Hybrid Fish

Abstract

Genetic hybrids of Xiphophorus fishes have been used for decades to study heritable melanoma formation. In these models, overexpression of pigmentation patterns from melanin-producing pigment cells can lead to genetically regulated melanoma formation in backcross hybrids. In the best studied of these models, the Gordon-Kosswig hybrid melanoma, tumors form spontaneously in all individuals of a subset of backcross hybrids between the platyfish Xiphophorus maculatus Jp 163 A and the swordtail species Xiphophorus helleri. Backcross hybrids susceptible to melanoma formation inherit a sex-linked oncogene, Xmrk, associated with the spotted dorsal (Sd) pigment pattern and have lost both copies of an autosomal gene, DIFF, from the X. maculatus parent. Spontaneous melanoma formation conforms to simple, two-gene Mendelian inheritance in which DIFF behaves as a recessive tumor suppressor gene. Recently, Xiphophorus hybrids in which melanomas can be induced by UV and near-UV visible light exposure have been described. We report here results of genetic linkage analysis of one of these Xiphophorus light-inducible hybrid melanoma models, in backcross hybrids between the two platyfish species X. maculatus Jp 163 B and Xiphophorus couchianus. Our linkage results provide the first estimate of recombination between the tumor suppressor locus, DIFF, and glycerate-2-dehydrogenase (GLYDH) in Xiphophorus linkage group V. Also, they demonstrate that DIFF regulates hyperplasia of spotted side (Sp) pigment cells in this hybrid model, analogous to its regulation of hyperplasia of Sd pigment cells in the "classical" Gordon-Kosswig hybrid. Joint segregation analyses of melanoma-bearing fish indicate that segregation of DIFF is genetically linked to melanoma induction by 405 nm light in this model but that induction of melanomas by UV wavelengths apparently does not depend on segregation of the DIFF locus.

A CDKN2 -like polymorphism in Xiphophorus LG V is associated with UV-B-induced melanoma formation in platyfish–swordtail hybrids

“…An additional marker, GLYDH, has been mapped between ES1 and MDH2 in LG V, again with variable recombination in different cross types ranging from 5-29% with MDH2 (37, 51). Recently, we analyzed the inheritance of pigmentation phenotypes and tumor susceptibility in another inducible Xiphophorus melanoma model, in backcross hybrids of the cross type Xiphophorus couchianus ϫ (X. maculatus Jp 163 B ϫ X. couchianus), which is informative for GLYDH (52). Our preliminary linkage analyses (unpublished data) of this hybrid indicate a gene order of GLYDH-CDKN2L1-ACTBL1, confirming the localization of CDKN2L1 in the DIFF region of LG V reported here.…”

Risk factors for development of internal neoplasms in koi carp Cyprinus carpio koi

“…Neoplasia is defined as uncontrolled proliferation and dispersal of autologous cells throughout the host body, resulting from accumulated DNA mutations (Martineau & Ferguson 2006). Some tumours in fish have been attri buted to genetic factors (Meierjohann & Schartl 2006, Nairn et al 1996; others were associated with a virus (Hanson et al 2011, Coffee et al 2013 or with environmental contamination (Fabacher & Baumann 1985, Baumann et al 1990, Harshbarger & Clark 1990. However, the presence of tumours in koi populations has not yet been extensively studied.…”

MNU Induction of Neoplasia in a Platyfish Model

“…F 1 hybrids and subsequently produced BC 1 hybrids show a pronounced phenotypic suppression of Sd, but an enhancement of Dr. The suppression of the Sd pigment pattern is a striking contrast to the severe enhancement of the Spot-sided (Sp) pigment pattern in a parallel genetic cross with the same parental species, but using X. maculatus strain Jp 163 B (Nairn et al, 1996b;Setlow et al, 1993Setlow et al, , 1989. In addition, the Sd pigment pattern itself, derived from X. maculatus strain Jp 163 A, is typically enhanced in numerous genetic crosses, including hybrids between X. maculatus and X. helleri.…”

“…Numerous crosses between parental strains have generated hybrid fish that develop melanomas with great predictability, both for anatomical position and age of onset. Melanomas derived within such hybrid crosses are clearly genetically predetermined, as was demonstrated for several Xiphophorus tumor models (Nairn et al, 1996b;Schartl, 1995;Vielkind et al, 1989). A candidate tumor suppressor gene, CDKN2X, which maps to Xiphophorus linkage group V (LG V) within a genomic region implicated in melanoma tumor suppression and pigment pattern regulation, was cloned (Kazianis et al, 1998(Kazianis et al, , 1999Vielkind, 1976).…”

“…Interspecific hybrid crosses between members of the fish genus Xiphophorus (currently comprising 22 species) have been used for over 70 years to study the genetic aspects of melanoma formation (Gordon, 1931a;Kosswig, 1927;Nairn et al, 1996b;Schartl, 1995). Typically, genetic traits, such as melanistic pigment patterns, are well regulated in the parental strains, but are inadequately regulated in hybrid fish, resulting in uncontrolled proliferation, and ultimately, in the development of neoplastic exophytic growths such as nodular melanomas.…”