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

Abstract

Progression of hepatocellular carcinoma (HCC) is a stepwise process that proceeds from preneoplastic lesions-including low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs)-to advanced HCC. The molecular changes associated with this progression are unclear, however, and the morphological cues thought to distinguish pre-neoplastic lesions from well-differentiated HCC are not universally accepted. To understand the multistep process of hepato-carcinogenesis at the molecular level, we used oligo-nucleotide microarrays to investigate the transcription profiles of 50 hepatocellular nodular lesions ranging from LGDNs to primary HCC (Edmondson grades 1-3). We demonstrated that gene expression profiles can discriminate not only between dysplastic nodules and overt carcinoma but also between different histological grades of HCC via unsupervised hierarchical clustering with 10,376 genes. We identified 3,084 grade-associated genes, correlated with tumor progression, using one-way ANOVA and a one-versus-all unpooled t test. H epatocelluar carcinoma (HCC) is one of the most common malignancies worldwide. The chronic hepatitis resulting from infection with hepatitis B virus or hepatitis C virus and exposure to carcinogens such as aflatoxin B1 are known as major risk factors for HCC. 1 Molecular investigations have recently found that genetic alterations of tumor suppressor genes or oncogenes such as p53, ␤-catenin, and AXIN1 might be involved in the progression to HCC, 2-4 but the frequency of these somatic mutations appears to be low in HCCs. Furthermore, it is unclear how these genetic changes reflect the clinical characteristics of the individual tumors. Therefore, the predominant molecular events underlying HCC in most patients remain unknown.Because HCC typically develops in close association with pre-existing cirrhosis, it is widely believed that a liver with cirrhosis may contain pre-neoplastic nodules that are in an intermediate stage between nonneoplastic regenerating nodules and overtly malignant HCC. 5,6 These nod-

Comparative and integrative functional genomics of HCC

“…As expected, prediction models based on gene expression profiles successfully discriminate HCC from non-tumor livers with expected high accuracy (Kim et al, 2004;Neo et al, 2004;Nam et al, 2005). Many studies have identified differentially expressed gene sets in HCC that differ according to etiological factors (Okabe et al, 2001), mutations of tumor suppressor genes (Chen et al, 2002), rate of recurrence (Iizuka et al, 2003), intrahepatic metastasis (Ye et al, 2003) and different stages (Nam et al, 2005).…”

Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growthin vitroandin vivo

“…We analyzed relative expression levels of PTTG1 between dysplastic nodule and grade II/III samples from microarray data 31,32 ( Fig. 1A).…”

Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas

“…Other recent studies also examined similarities between HCC precursor lesions (low and high grade liver nodules) and demonstrated significant similarities but also differences between HCC and precursor lesions. 5 In this study, we also focused on gene expression of HCC and HPBL, but from a different perspective than previous studies. We utilized a set of tissues from normal liver (NL), HCC, HPBL and tumor adjacent (AT) tissues and determined gene expression patterns not as a ratio of tumor vs. normal, but rather as absolute separate values for each unique tissue.…”