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. Because 85% or more of hepatocellular carcinoma (HCC) occur in cirrhotic livers in Western patients, 1 it is possible that certain cirrhotic nodules (CNs) could become preneoplastic. This could be followed, putatively, by the appearance of dysplastic nodules (DNs) and HCCs. A body of evidence resulting from histology 2 and imaging modalities 3 has, over the past decade, documented the relationship between the dysplastic nodular lesions seen mostly in cirrhotic livers and HCC. [2][3][4] DNs have been classified as low-grade (LGDN) and highgrade (HGDN) according to the criteria proposed by the International Working Party. 5 LGDNs have mild atypia, while HGDNs have one or more of the following: high nuclearcytoplasmic ratio, nuclear hyperchromasia, irregular nuclear contour, plates more than 2 cells wide, pseudoglandular formation, cytoplasmic basophilia, and resistance to iron accumulation. 5 However, the molecular mechanisms implicated in this progression remain unknown. Because of the lack of markers for early genetic changes, the only direct evidence at the molecular level for a DN3 HCC sequence has come from the integrated pattern of hepatitis B virus (HBV) DNA of a HCC located within an HGDN (a so-called "nodule-in-nodule" lesion) in a cirrhotic liver. 6 In this study, the HGDN and HCC were from an identical clone. Examination of the mechanisms of transformation of DN would be more feasible if other early molecular markers were to be found.

Hepatitis B Virus–Associated Multistep Hepatocarcinogenesis: A Stepwise Increase in Allelic Alterations

“…Although LOH was observed at z1 of the 19 loci in 70.8% of the cirrhotic livers, the mean FAL index was low, at 0.09. This low incidence of allelic losses was consistent with those in previous reports (11,13,18) and also our previous report on mostly HBVassociated cirrhotic livers but with concomitant HCC (17). From the previous reported series, the FAL indices in cirrhosis vary from 0.05 to 0.15 (11,13,18).…”

“…In general, the genetic profile of liver DNs is poorly understood. There are only a few reports on the allelic or chromosomal changes of DNs in the literature (10)(11)(12)(13). However, in most of these reports, only a small number of chromosomes were examined.…”

Identification of Four Distinct Regions of Allelic Imbalances on Chromosome 1 by the Combined Comparative Genomic Hybridization and Microsatellite Analysis on Hepatocellular Carcinoma

“…Frequent LOH on chromosome 1p36 has been implicated in the progression of intrahepatic cholangiocarcinoma, the second most common liver malignancy (11), and has also been well documented in neuroblastomas (12). Although allelic losses on 1p36 have been suggested to be associated with poor differentiated histologic grade in epithelial ovarian carcinoma (13), deletions on 1p36.12 were found in the early dysplastic lesions and cirrhotic nodules of hepatocellular carcinoma (7). A role for 1p36 deletions in the early events of hepatocarcinogenesis was thus further enforced.…”

“…Using CGH, we and others have detected recurrent gains of 1q, 6p, 8q, 17q and 20q and losses of 1p, 4q, 8p, 13q, 16q and 17p (4 -6). Among the common aberrations observed, loss of heterozygosity (LOH) of 1p36 -p34 has been identified in the putative premalignant cirrhotic nodules and, by using centromeric probes, chromosome 1 polysomy has been reported in liver dysplasia by interphase cytogenetics (7,8). Thus, deletions on distal 1p and 1q copy gains have been implicated in the early stages of hepatocellular carcinoma development.…”

Up-regulated expression of stathmin may be associated with hepatocarcinogenesis

“…It is encoded by the human STMN1 gene located at chromosome 1p36.1 which is related to high frequency of allelic loss in HCC (4). HCC exhibits frequent chromosomal losses in 1p, 4q, 16q and 17p (5-7), especially in 1p36, which include 1p36.1 (8), 1p36.13-p36.23 (9,10) and 1p36.2-p36.3 (11,12).…”