Genetic basis of susceptibility for neuroblastoma following treatment with N-methyl-N-nitrosourea and X-rays in Xiphophorus.

INTRODUCTION In 65 genotypes of Xiphophorus (nonhybnids and inter populational and interspecific F and backcnoss hybrids), the susceptibility to neuroblastoma following treatment with carcinogenic-mutagenic agents was tested. The fish were exposed to an aqueous solution of N-methyl-N-n itro sounea (MNU) or exposed to X-rays. Neunoblastoma was induced by MNU in 64 of about 3500 treated fish and by X nays in 4 of about 5500 treated fish; in the control fish, as well as in the vast number of fish routinely bred in our fish laboratory during the last 20 years, neunoblastoma was not observed. Sixty of the 64 MNU-induced neuroblastomas and all 4 X-ray-induced neuroblastomas developed in the 605 and 859 treated fish, respectively, of a group of back cross genotypes carrying the “lineatus― chromosome. These fish are derived from Xiphophorus variatus x Xipho phorus helleri hybrids with X. helleri as the recurrent parent. The remaining four cases of neuroblastoma induced by MNU were distributed at random throughout fish of back cross genotypes derived from other species; within these, a relationship to the genotype is not detectable. In both X. variatus and the F (X. variatus x X. helleri), although carrying the same lineatus chromosome, as well as in X. helleri lacking this chromosome and in the lineatus-lacking segnegants, from each of which a comparable number of fish was treated, neuroblastoma could not be induced. The results are interpreted to imply that the neuroblastoma is triggered by somatic mutation of regulating genes sup pressing another gene that favors neoplastic transformation and that is located on the lineatus chromosome. The differential susceptibility of the fish carrying this chromo some (X. variatus, F , and backcross hybrids) might depend on the number of regulating genes. Accordingly, insuscep tibility, as in the case of X. variatus, would be due to a polygenic regulating system, which, in practice, cannot be impaired in one cell. Susceptibility, as in the case of the lineatus backcross segnegants, would be due to a mono genic regulating system, which can easily be impaired by one single mutation, and this monogenic state of regulation may be achieved by elimination of regulating genes in the course of selective backcrossing. , This work was supported by Deutsche Forschungsgemeinschaft through Sonderforschungsbereich 103 †̃Zellenergetikund Zelldifferenzierung' (Proj ects C 11 and C 12), Marburg; and by Land Hessen through Justus-Liebig Universitaet Giessen. This work is dedicated to Peter Karlson on the occasion of his 60th birthday. This paper contains parts of the dissertations of Gerhard Kollinger, Joachim Haas, and Safia Abdo. 2 To wham requests for reprints should be addressed. 3Onleave fromtheUniversity ofAlexandria; supported bytheEgyptian Ministry of Education. Received August 11, 1978; accepted October 23. 1978. Certain interpopulational and interspecific hybrids be tween the platyfish (Xiphophorus maculatus) and the swordtail (Xiphophorus helleri) spontaneously develop mel anomas (20, 21, 24, 36), thyroid tumors (41), or ocular tumors (22). Subsequent analysis of melanomas as well as other neoplasms of Xiphophorus has led to the suggestion that development of a neoplasm may result from a mis guided expression of an endogenous entity capable of transforming cells from the normal to the neoplastic state (4-6). This entity was called Tu4 (7). Tu appears to be present in all populations and species of Xiphophorus and may exist in an individual in multiple form distributed oven several chromosomes. Although the nature and the biolog ical function of Tu are still largely obscure, some specula tions on these aspects of Tu have been presented recently (2-4). The present investigation is part of a broad-scale expeni ment in which a large number of defined genotypes were tested for their susceptibility to develop neoplasms follow ing treatment with mutagenic-cancinogenic agents (1, 9, 10, 23, 35, 47-51 ). We have tested the susceptibility with 2 basically different types of agents, namely, a chemical agent, MNU, which is a direct-acting mutagen-carcinogen not requiring metabolic activation (37, 40, 42), and a physi cal agent, X-nays. Both exert their carcinogenic effect most likely via mutation (for MNU, see Refs. 15 and 28; for X-nays, see Refs. 13 and 17). This experiment has shown thus fan, that, following exposure to both agents, various neoplasms can be induced, including melanoma, neunoblastoma, squamous cell carcinoma, epithelioma, carcinoma, adeno carcinoma, papilloma, hepatoma, fibrosarcoma, rhabdom yosarcoma, and lymphosancoma; the susceptibility to 5ev eral of these neoplasms appears to be confined to particular chromosomes (49, 51). In a previous paper, we have pne sented data on the susceptibility to both the fibrosancoma and rhabdomyosarcoma (49). This report deals with the susceptibility to neuroblastoma. MATERIALS AND METHODS