Frequent loss of heterozygosity at the Hcr1 (hepatocarcinogenesis resistance) locus on chromosome 10 in primary hepatocellular carcinomas from LFF1 rat strain

Hepatocarcinogenesis sensitivity (Hcs1,2) and resistance (Hcr1-3) loci have been identified by linkage analysis on rat chromosomes 7 and 1, and 10, 4, and 8, respectively. Cytogenetic studies documented deletions on chromosom es 3 and 6 of neoplastic rat hepatocytes. Hepatocellular carcinomas (HCCs) were produced in F1 hybrid rats between Long-Evans (LE) and Fisher 344 (F34 4) rats. Scanning of the above chromosomes for loss of heterozygosity (LOH) showed allelic imbalance (AI) at multiple regions on chromosomes 6, 7, and 10q. Detailed deletion mapping of chromosome 10 localized a putative suppr essor Hcr1 gene to within a 3.2-cM interval flanked by D10Rat51 and D10Rat1 21. Two other distinct regions with frequent AIs were found inside the Hcr1 locus, at marker loci including DNaseI and Mrp genes, and in a segment inc luding 4 consecutive markers (D10Rat64, D10Rat182, D10Rat113, D10Rat216). I n 40% of HCCs, AI was seen at the p53 locus. AI on chromosome 7 occurred at the Hcs1 locus, where is located c-myc, which is amplified in HCCs, sugges ting allelic gain. Most AIs occurred in poorly/moderately differentiated ca rcinomas, and a few events were seen in well-differentiated tumors on chrom osomes 7 and 10. These data suggest that alteration of a cluster of oncosup pressor genes on 10q is important for HCC progression. The existence of AI on segments of rat chromosomes 6, 7, and 10, syntenic to chromosomal segmen ts of human HCCs where chromosomal gains or deletions occur, suggests a com monalty of some molecular events in the pathogenesis of HCCs in rats and hu mans. Our map provides information toward cloning putative oncosuppressor g enes associated with this carcinoma.