Shian-Yang Peng

β-Catenin Mutations Are Associated with a Subset of Low-Stage Hepatocellular Carcinoma Negative for Hepatitis B Virus and with Favorable Prognosis

To better understand the role of beta-catenin mutation in hepatocellular carcinoma (HCC), we correlated the gene mutation with hepatitis virus B (HBV) and hepatitis virus C (HCV) status and the clinicopathological features in 366 patients with resected primary unifocal HCC. beta-Catenin mutations were also analyzed in 55 patients with multifocal HCC (68 tumors). Of the whole series, 57 (13.1%) of 434 tumors examined had beta-catenin mutations, 34 occurred at the serine/threonine residues of the GSK-3beta region of beta-catenin. Outside the GSK-3beta phosphorylation site, codons 32 and 34 were two mutational hot spots (17 tumors). The non-HBV-related HCC that was predominantly HCV related had a higher frequency of mutation (P: < 0.00001) and more frequent mutations at codon 45 than HBV-related HCC. HBV-related HCC had a younger mean age (P: < 0.00001), and higher male-to-female ratio (P: < 0.003) and positive familial history of HCC (P: < 0.014). Among 366 unifocal HCCs selected for clinicopathological analysis, beta-catenin mutations were associated with grade I (P: = 0.005) and stage I and II HCC (P: < 0.0001), and a better 5-year survival rate (P: = 0. 00003). These findings suggest mechanisms for beta-catenin mutations differ between HBV-related and non-HBV-related HCCs, and that beta-catenin mutation is a favorable prognostic factor related to low stage. beta-Catenin mutation was associated with nuclear expression of the protein (P: < 0.00001), but we failed to detect point or large fragment deletion mutation in 39 HCCs with nuclear beta-catenin expression, presumably wild-type protein. HCCs expressing mutant nuclear beta-catenin had a better 5-year survival rate (P: < 0.007), suggesting that mutant and wild-type nuclear beta-catenin proteins are not functionally equivalent and deserve more studies for further clarification.

Overexpression and Amplification of Aurora-A in Hepatocellular Carcinoma

Purpose: Aurora-A/STK15/BTAK, a centrosome-associated serine/threonine kinase, has been shown to induce chromosomal instability, leading to aneuploidy and cell transformation. The purpose of this study was to investigate the expression and amplification of Aurora-A in hepatocellular carcinoma (HCC). Experimental Design: Aurora-A mRNA levels were measured in 224 HCCs and 199 paired nontumorous liver tissues by reverse transcription-PCR. Aurora-A mRNA and protein levels of 8 were also measured by reverse transcription-PCR and Western blot hybridization in 8 liver cancer cell lines. Amplification of Aurora-A was determined by Southern blot hybridization in 99 cases. Results: Aurora-A was overexpressed in 137 of 224 (61%) HCCs and all 8 of the cell lines. Overexpression of Aurora-A was associated with high-grade (grade II-IV), and high-stage (stage IIIB-IV) tumors, p53 mutation, infrequent β-catenin mutation, and poor outcome. Aurora-A overexpression and p53 mutation acted synergistically toward poor prognosis. Amplification of Aurora-A was detected only in 3 HCCs. Conclusion: The results show that Aurora-A is overexpressed frequently in HCC, and correlated with high grade and high stage, indicating that overexpression of Aurora-A plays a role in the development and progression of HCC.

High α‐fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: Significance of hepatitis virus infection, age, p53 and β‐catenin mutations

α‐Fetoprotein (AFP) is often elevated in hepatocellular carcinoma (HCC). This study was to elucidate the significance and related factors of AFP elevation in HCC in 781 unifocal HCCs receiving curative hepatectomy. We showed that high AFP (> 200 ng/ml), which was associated with AFP mRNA expression in HCC (p = 0.00001), correlated with major clinicopathologic factors. Younger age (≤ 55 years; p = 0.00001), hepatitis B surface antigen (HBsAg) in serum (p = 0.00001), p53 mutation (p = 0.008), large tumor (p = 0.00001), vascular invasion (p = 0.00001) and early tumor recurrence (p = 0.00001) were significant associates of high AFP, while anti‐HCV in serum and β‐catenin mutation in HCC had less frequent high AFP (p = 0.013 and < 0.0001, respectively). We also showed that HCC with high AFP had a lower 10‐year survival (p < 0.0001), particularly in large HCC (p < 0.0001). At univariate analysis, high AFP (p < 0.0001), HBsAg positivity (p = 0.05), p53 mutation (p = 0.0004), liver cirrhosis (p = 0.0094), large tumor (p = 0.0003), vascular invasion (p < 0.0001) and early recurrence (p < 0.0001) were significant unfavorable prognostic factors. In Cox proportional hazards regression analysis, high AFP remained a borderline significance (OR = 1.2; CI = 1.0–1.4) after adjustment for the effect of tumor size and tumor stage (p = 0.0821). Furthermore, the detection of AFP mRNA in the liver of AFP mRNA‐positive HCC was associated with more frequent early recurrence (p = 0.0026) and might be a useful marker of intrahepatic spread. We therefore conclude that AFP elevation, more than a coincidental epiphenomenon, appears to contribute to vascular invasion and HCC progression and help to identify subsets of HCC patients with increased risk for early recurrence and poor prognosis after hepatectomy.

Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma

Intrahepatic metastasis via portal vein spread is an important feature and a crucial unfavorable prognostic factor of hepatocellular carcinoma (HCC). To identify the molecular factors for tumor progression, the authors used differential display (DD) to analyze aberrant gene expression in HCC. The goal of the current study was to elucidate the clinicopathologic and prognostic significance of osteopontin (OPN) in HCC progression.

ASPM Is a Novel Marker for Vascular Invasion, Early Recurrence, and Poor Prognosis of Hepatocellular Carcinoma

Purpose:Abnormal spindle-like microcephaly associated (ASPM) plays an important role in neurogenesis and cell proliferation. This study is to elucidate its role in hepatocelllular carcinoma (HCC), particularly early tumor recurrence (ETR) and prognosis. Experimental Design: We used reverse transcription-PCR assays to measure the ASPM mRNA levels in 247 HCC and correlated with clinicopathologic and molecular features. Results:ASPM mRNA levels were high in fetal tissues but very low in most adult tissues. ASPM mRNA was overexpressed in 162 HCC (66%) but not in benign liver tumors. ASPM overexpression correlated with high α-fetoprotein (P = 1 × 10-8), high-grade (grade II-IV) HCC (P = 2 × 10-6), high-stage (stage IIIA-IV) HCC (P = 1 × 10-8), and importantly ETR (P = 1 × 10-8). ETR is the most critical unfavorable clinical prognostic factor. Among the various independent histopathologic (tumor size, tumor grade and tumor stage) and molecular factors (p53 mutation, high α-fetoprotein, and ASPM overexpression), tumor stage was the most crucial histologic factor (odds ratio, 14.7; 95% confidence interval, 6.65-33.0; P = 1 × 10-8), whereas ASPM overexpression (odds ratio, 6.49; P = 1 × 10-8) is the most important molecular factor associated with ETR. ASPM overexpression was associated with vascular invasion and ETR in both p53-mutated (all P values = 1 × 10-8) and non-p53-mutated HCC (P = 1 × 10-8 and 0.00088, respectively). Hence, patients with APSM-overexpressing HCC had lower 5-year survival (P = 0.000001) in both p53-mutated (P = 0.00008) and non-p53-mutated HCC (P = 0.0027). In low-stage (stage II) HCC, ASPM overexpression also correlated with higher ETR (P = 0.008). Conclusion:ASPM overexpression is a molecular marker predicting enhanced invasive/metastatic potential of HCC, higher risk of ETR regardless of p53 mutation status and tumor stage, and hence poor prognosis.

Allelotype and loss of heterozygosity of p53 in primary and recurrent hepatocellular carcinomas. A study of 150 patients

Background. The allelotype and loss of heterozygosity (LOH) of the p53 gene in human hepatocellular carcinoma (HCC) were studied in 150 patients with resected primary HCC and 18 with recurrent HCC.

Expression and prognostic significance of gastric-specific annexin A10 in diffuse- and intestinal-type gastric carcinoma

Background and Aims:  Annexin A10 (ANXA10) and its liver‐specific short isoform (ANXA10S) had tissue‐restricted expression. The downregulation of ANXA10S is correlated with tumor progression and poor prognosis in hepatocellular carcinoma. The aim of the present study was to validate the tissue distribution and explore the role of the ANXA10 protein expression in gastric carcinoma.

ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila))

Review on ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila)), with data on DNA, on the protein encoded, and where the gene is implicated.