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

• Published in: Cancer research (Chicago, Ill.) Vol. 59; no. 18; pp. 4651 - 4657
• Main Authors: DE MIGLIO, M. R, CANZIAN, F, PASCALE, R. M, SIMILE, M. M, MURONI, M. R, CALVISI, D, ROMEO, G, FEO, F
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.1999
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Carcinogens - toxicity; chromosome 10; chromosome 4; chromosome 7; chromosome 8; Chromosome Mapping; Crosses, Genetic; Diethylnitrosamine - toxicity; Experimental digestive system and abdominal tumors; Female; Genetic Markers; Genetic Predisposition to Disease; Genotype; Liver - drug effects; Liver - pathology; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - pathology; Male; Medical sciences; Phenotype; Rats; Rats, Inbred BN; Rats, Inbred F344; Tumors; Genetic mapping; Animal model; Rat; Rodentia; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Chromosome C10; Chromosome C7; Carcinogen; Vertebrata; Mammalia; Animal; C-Onc gene; Digestive diseases; Genetics; Locus
• ISSN: 0008-5472; 1538-7445

Neoplastic liver nodules and hepatocellular carcinomas (HCCs) were induced, by "resistant hepatocyte" model, 32 and 70 weeks after initiation with diethylnitrosamine, respectively, in F344 Brown Norway (BN), and (BNxF344)F1 rats. Nodule number/liver (N) did not significantly differ among rat strains, whereas nodule mean volume (V) and nodule volume fraction (VF) were higher in susceptible F344 than in resistant BN and BFF1 strains and were predictive of subsequent development of HCCs. Genomic scanning of 157 backcross BFF1xF344 rats with 190 polymorphic microsatellites, and linkage analysis, revealed two quantitative trait loci (QTL) on chromosomes 7 and 10, which showed 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 patterns of homozygous and heterozygous backcross progeny and of allelic distribution pattern, QTL on chromosomes 10, 8, and 4 were tentatively identified as 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 an additive effect of loci on chromosomes 10, 8, and 4 for VF and V. These data are the first to identify chromosomal regions containing putative susceptibility/resistance loci for rat hepatocarcinogenesis, which seems to be highly complex in terms of the number of genetic factors involved.