Identification of genetic loci controlling hepatocarcinogenesis on rat chromosomes 7 and 10

Neoplastic liver nodules and hepatocellular carcinomas (HCCs) mere induced, by "resistant hepatocyte" model, 32 and 70 weeks after initiation with die thylnitrosamine, respectively, in F344 Brown Norway (BN), and (BNxF344)F1 r ats. Nodule number/liver (N) did not significantly differ among rat strains , whereas nodule mean volume (V) and nodule volume fraction (VF) were highe r in susceptible F344 than in resistant BN and BFF1 strains and were predic tive of subsequent development of HCCs. Genomic scanning of 157 backcross B FFIxF344 rats with 190 polymorphic microsatellites, and linkage analysis, r evealed two quantitative trait loci (QTL) on chromosomes 7 and 10, which sh owed significant linkage with VF, and two QTL on chromosomes 4 and 8, which showed suggestive linkage with V and VF. On the basis of phenotypic patter ns of homozygous and heterozygous backcross progeny and of allelic distribu tion pattern, QTL on chromosomes 10, 8, and 4 mere tentatively identified a s resistance loci, and QTL on chromosome 7 was identified as susceptibility locus for rat hepatocarcinogenesis. An analysis of interactions allowed us to identify additional putative QTL on chromosomes 5 and 8 and suggested a n additive effect of loci on chromosomes 10, 8, and 4 for VF and V. These d ata are the first to identify chromosomal regions containing putative susce ptibility/resistance loci for rat hepatocarcinogenesis, which seems to be h ighly complex in terms of the number of genetic factors involved.