Chromosomal Alterations in Hepatocellular Nodules by Comparative Genomic Hybridization: High-Grade Dysplastic Nodules Represent Early Stages of Hepatocellular Carcinoma

Abstract

SUMMARY:Data from experimental hepatocarcinogenesis and recent studies in humans have suggested that the emergence of hepatocellular carcinoma (HCC) is a stepwise process. However, despite abundant experimental data, the precise molecular mechanisms and genetic alterations involved in human liver carcinogenesis are still unclear. Comparative genomic hybridization was used to analyze 26 hepatocellular nodules obtained from patients undergoing liver transplantation or surgical resection for HCC. According to the criteria proposed by the International Working Party, 16 nodules were classified as multiacinar regenerative nodules (MRN), 4 as low-grade dysplastic nodules (LG-DN), and 6 as high-grade dysplastic nodules (HG-DN). Our aim was to investigate the possible genetic differences between MRN, LG-DN, and HG-DN. The whole group of nodules showed only a few aberrations (mean 1.1/case), without any significant pattern. This finding is comparable to what happens in non-neoplastic tissue. On the contrary, in three of six HG-DN, we found deletions of 8p and gains of 1q.LG-DN and MRN did not show these chromosomal imbalances. These results confirm the important role of allelic losses on 8p as well as of gains of 1q in HCC. We conclude that the genes that are important in early stages of hepatocarcinogenesis are probably located on these chromosomal arms. (Lab Invest 2002, 82:547-553).

Pattern of chromosomal aberrations in primary liver cancers identified by comparative genomic hybridization

“…The present results support chromosomal gains at 1q and 8q and losses at 8p to represent characteristic chromosomal imbalances during HCC carcinogenesis, of which gains at 1q and 8q have been identified as early events in HCC [16] and preneoplastic lesions of HCC [17,18]. In a genetic tumor progression model constructed from CGH data of 158 hepatitis B virus-associated HCC cases, gains at 1q and 8q were identified as the earliest cytogenetic aberrations, whereas losses at 8p and 17p were regarded as events occurring at intermediate stages, and gains at 3q as late events in HCC progression [16].…”

Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis

“…This feature is in keeping with that reported in unequivocally nonmalignant hepatocellular nodules [5][6][7] and supports the contention that LGDNs are more related to regenerative rather than dysplastic/ premalignant nodules. 29 Our results further emphasize that the expression of the markers is restricted to the advanced stages of hepatic carcinogenesis and that their use should be considered when facing morphologically atypical hepatocellular lesions, when it is uncertain whether they are malignant or dysplastic. Indeed, in this study, we found HSP70, GPC3, and GS expression largely restricted to the vast majority of HCCs.…”

Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling

“…7 That these nodules frequently contain one or more microscopic foci of HCC suggests that dysplastic nodules, especially HGDNs, might be precancerous lesions of HCC. 8,9 Some investigators have adopted the concept of early HCC (eHCC)-sometimes referred to as "carcinoma in situ" or "microinvasive carcinoma" of the liver-which is characterized by a small tumor mass lacking invasive growth properties such as vascular invasion or intrahepatic metastasis. [10][11][12] However, there remains considerable controversy as to whether eHCC should be regarded as frank cancer or as a form of HGDN.…”