Regional over-representations on chromosomes 1q, 3q and 7q in the progression of hepatitis B virus-related hepatocellular carcinoma

Abstract

Hepatocellular carcinoma is a highly malignant tumor that is prevalent in Southeast Asia and China, where hepatitis B viral infection is the main etiologic factor. Despite a high incidence of hepatocellular carcinoma developing in patients with viral hepatitis B-induced liver cirrhosis, the molecular events underlying the malignant liver progression remain largely unclear. In an effort to characterize the genetic abnormalities involved in the hepatitis B-related liver carcinogenesis, we performed genome-wide explorations by the technique of comparative genomic hybridization (CGH) on 100 hepatocellular carcinoma tumors that arose from hepatitis B-induced liver cirrhosis. According to the American Joint Committee on Cancer staging, four cases were classified as stage I, 69 as stage II, 23 as stage III and four as stage IV. CGH analysis indicated chromosomal instability in both early (stages I/II) and advanced (stages III/IV) stage tumors, with common gains on 1q, 8q and 17q23-q25, and losses on 4q22-q35, 8p21-p22, 13q14-q21, 16q and 17p identified in both groups (P40.05). Nevertheless, preferential sites of chromosomal defects in relation to hepatocellular carcinoma progression were also identified. Statistical correlations suggested a higher incidence of regional 1q21-q22, 3q22-q28, 7q21-q22 and 7q34-q36 over-representations in association with the advanced stage tumors (Po0.05). In this study, our novel identification of specific chromosomal aberrations in relation to the advanced stage tumors may represent a first step towards mapping genes linked to the progression of hepatocellular carcinoma. Modern Pathology (2005) 18, 686-692, advance online publication, 17 December 2004; doi:10.1038/modpathol.3800345 Keywords: hepatocellular carcinoma; hepatitis B virus; liver cirrhosis; progression Hepatocellular carcinoma is a primary liver malignancy that is highly malignant and rapidly fatal. The dismal clinical outcome is largely due to the majority of hepatocellular carcinoma tumors being asymptomatic during the natural course of the disease, consequently rendering most patients not being diagnosed in time for curative surgery. 1 By the time of clinical presentation, intra-and extrahepatic metastases are also common, which in turn has limited the scope of curative surgery. 2 In addition, the relatively high incidences of hepatocellular carcinoma recurrence, possibly from micrometastasis prior to surgical treatment, has further lowered the 5-year survival rate for individuals diagnosed with hepatocellular carcinoma. 3 The understanding of molecular events involved in the malignant liver progression thus would hold much value in the prognosis for patients with hepatocellular carcinoma.Studies on the molecular pathogenesis have guided the development of gene-based biomarkers in a number of human cancers including breast, colon, prostate and lung. 4 In hepatocellular carcinoma, although genetic characterizations have indicated frequent chromosomal over-representations on 1q, 6p, 8q, 17q and 20q, and deletions on 1p, 4q, ...

Identification ofPFTAIREprotein kinase 1, a novel cell division cycle-2 related gene, in the motile phenotype of hepatocellular carcinoma cells

“…Dual-color fluorescence in situ hybridization (FISH) analysis was performed according as previously described. 18 Human bacterial artificial chromosome CTB-141D22 that embodied the PFTK1 gene and a reference clone RP11-110A23 on chr1p31.3 that seldom displayed imbalances in HCC 7 were differentially labeled with biotin-dUTP and digoxigenin-dUTP, respectively. Hybridized signals onto fixed cells of direct harvests or short-term cultures of primary HCC were visualized with avidin-conjugated FITC (Sigma, St Louis, MO), and anti-digoxigenin conjugated TRITC antibodies (Sigma).…”

“…7q21-q22, to be closely associated with the advanced metastatic tumors. 7 Gains on the proximal 7q11.2-q31 have also been associated with metastatic colorectal carcinoma 8 and with the increased tumor vascularizations of prostate cancers. 9 In sporadic Burkitt's lymphoma 10 and esophageal squamous cell carcinoma, 11 gains of 7q with the smallest overlapping region mapped to 7q21-q22 have also been correlated with advanced pathological staging and shorter patient survivals.…”

Loss of 13q is associated with genes involved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma

“…These aberrations have been correlated with etiological factors such as viral (hepatitis B, hepatitis C) infections. [12][13][14] Clinical impact has been reported for losses of 8p and gain of 20q with respect to stage and prognosis. 15 On the basis of genomic alterations detected by aCGH, hepatocellular carcinoma and its benign counterpart, hepatocellular adenoma, could be differentiated.…”

Novel identification of zyxin upregulations in the motile phenotype of hepatocellular carcinoma

“…Our group has previously conducted largescale correlative analysis on the genomic data derived from early and advanced stages hepatocellular carcinoma tumors with an aim to define the genetic aberrations involved in disease progression. 4 A number of regional copy gains were indicated, among which chromosome 7q34-q36 gains were common in the advanced metastatic hepatocellular carcinoma. 4 Distal chromosome 7q gains have been suggested in association with biliary tract carcinoma progression, 5 and higher-stage non-small cell lung cancer with nodal involvement.…”

“…4 A number of regional copy gains were indicated, among which chromosome 7q34-q36 gains were common in the advanced metastatic hepatocellular carcinoma. 4 Distal chromosome 7q gains have been suggested in association with biliary tract carcinoma progression, 5 and higher-stage non-small cell lung cancer with nodal involvement. 6 Previous studies have also demonstrated a positive association between prostate cancer progression and copy gains of distal chromosome 7q, 7 and the amplification of chromosome 7q31-q36 region in the progression of gliomas to grade III or IV.…”