Gastroenterology

Gastroenterology

Volume 133, Issue 5, November 2007, Pages 1475-1486
Gastroenterology

Clinical–Liver, Pancreas, and Biliary Tract
Genetically Distinct and Clinically Relevant Classification of Hepatocellular Carcinoma: Putative Therapeutic Targets

https://doi.org/10.1053/j.gastro.2007.08.038Get rights and content

Background & Aims: The biological aggressiveness of hepatocellular carcinoma (HCC) and the lack of optimal therapeutic strategies have rendered the disease a major challenge. Highly heterogeneous genetic alteration profiles of HCC have made it difficult to identify effective tailor-made molecular therapeutic targets. Therefore, classification of HCC into genetically homogeneous subclasses would be of great worth to develop novel therapeutic strategies. Methods: We clarified genome-scale chromosomal copy number alteration profiles and mutational statuses of p53 and β-catenin in 87 HCC tumors. We investigated the possibility that HCC might be classifiable into a number of homogeneous subclasses based solely on their genetic alteration profiles. We also explored putative molecular therapeutic targets specific for each HCC subgroup. Results: Unsupervised hierarchical cluster analysis based on chromosomal alteration profiles suggested that HCCs with heterogeneous genetic backgrounds are divisible into homogeneous subclasses that are highly associated with a range of clinicopathologic features of the tumors and moreover with clinical outcomes of the patients (P < .05). These genetically homogeneous subclasses could be characterized distinctively by pathognomonic chromosomal amplifications (eg, c-Myc–induced HCC, 6p/1q-amplified HCC, and 17q-amplified HCC). An in vitro experiment raised a possibility that Rapamycin would significantly inhibit the proliferative activities of HCCs with 17q amplification. Conclusions: HCC is composed of several genetically homogeneous subclasses, each of which harbors characteristic genetic alterations that can be putative tailor-made molecular therapeutic targets for HCCs with specific genetic backgrounds. Our results offer an opportunity for developing novel individualized therapeutic modalities for distinctive genome types of HCC.

Section snippets

Human Tissue Samples

Tissue samples of HCCs and paired nontumorous liver tissues were obtained from 87 patients undergoing partial hepatectomy between October 1993 and February 2001 at the National Cancer Center Hospital (Table 1). Specimens were taken immediately after surgery, fixed with 100% methanol, and embedded in paraffin. Informed consent was obtained from each patient, and this study was approved by the institutional review boards of the National Cancer Center.

DNA Preparation and Array CGH Analysis

Laser capture microdissection and DNA

Genome-Scale Profiling of Chromosomal Structural Alterations in HCC and Novel Chromosomal Alterations

Figure 1 shows a global view of the chromosomal alteration profiles of the 87 HCCs revealed by array CGH analysis. Chromosomal losses such as on 1p, 4q, 6q, 8p, 10q, 13q, 16p/q, 17p, and Y (male), and chromosomal gains such as on 1q, 6p, 7p/q, 8q, 17q, 19p/q, 20p/q, and Xq (male) were observed highly frequently (more than 25.0% of all cases). Homozygous deletions and recurrent chromosomal amplifications among our cohort are indicated in Figure 1 and listed in supplementary Table 2 (see

Discussion

To delineate the heterogeneity of genetic alterations among HCCs, we performed unsupervised clustering analysis based on chromosomal alteration patterns in the tumors. Hierarchical clustering of the data revealed 2 major HCC subclasses, clusters A and B, that were associated significantly with clinical features, such as HBV infection, higher serum α-fetoprotein levels, and a higher incidence of intrahepatic metastasis, and, furthermore, the shorter overall patient survival (Figure 3 and Table 1

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    Supported in part by a grant-in-aid for the Comprehensive 10-Year-Strategy for Cancer Control from the Ministry of Health, Labor and Welfare, Japan; and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, Tokyo, Japan.

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    Copyright © 2007 AGA Institute. Published by Elsevier Inc. All rights reserved.