An early lesion in hepatic carcinogenesis: loss of heterozygosity in human cirrhotic livers and dysplastic nodules at the 1p36-p34 region.

ABSTRACT

Loss of heterozygosity (LOH) of chromosome 1 has been suggested, by karyotyping, to be an initial episode in human hepatocarcinogenesis. However, this alteration has not yet been investigated in cirrhotic nodules (CNs) or dysplastic nodules (DNs). In an initial study from explanted or resected cirrhotic livers, LOH in 1p36-p32 was examined in 31 hepatocellular carcinomas (HCCs), 25 low-grade dysplastic nodules (LGDNs), and 24 high-grade dysplastic nodules (HGDNs). In HCCs, LOH was detected most frequently at loci D1S2843 (1p36.1) (28.6%), D1S513 (1p34.3) (29.2%), and MYCL1 (1p34.1) (28.6%). In HGDN and LGDN, LOH incidences at D1S513 were 11.1% and 13.6%, respectively. To further refine those results and to determine sequential relationships among CN, DN, and HCC, LOH was next studied in an additional 53 HCCs, 56 HGDNs, 30 LGDNs, and 215 CNs from 11 explanted human cirrhotic livers, including 30 "nodule-in-nodule" lesions. Seven markers between D1S2843 (1p36.12) and MYCL1 (1p34.1), and 1 each at D1S484 (1q24.1), IGF2R-3 (6q26), and TP53 (17p13.1) were used. LOH at D1S2843 and D1S513 was detected in HCCs (20.4% and 23.5%, respectively), HGDNs (7.7% and 18.5%), LGDNs (13.6% and 6.9%), and CNs surrounding either HCCs or DNs (7.4% and 8.3%). These results demonstrate that LOH at D1S2843 and D1S513 are early events in human liver carcinogenesis. Data from CN surrounding either HCCs or DN, and also nodule-in-nodule lesions, provide evidence supporting a CN-->DN-->HCC progression. Different deletion patterns from multiple HCCs and DNs suggest independent origins for carcinogenesis in the same individual.