MICROARRAYS AND OTHER NEW TECHNOLOGIES A Tumor Progression Model for Hepatocellular Carcinoma: Bioinformatic Analysis of Genomic Data TERENCE C. W. POON,* ,‡ NATHALIE WONG, § PAUL B. S. LAI,  MAGNUS RATTRAY, ‡ PHILIP J. JOHNSON, ¶ and JOSEPH J. Y. SUNG* Departments of *Medicine and Therapeutics, § Anatomical and Cellular Pathology, and  Surgery, Sir Y. K. Pao Cancer Centre, the Chinese University of Hong Kong, Prince of Wales Hospital, N. T., Hong Kong, The People’s Republic of China; ‡ School of Computer Science, University of Manchester, Manchester, United Kingdom; and ¶ Cancer Research UK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, United Kingdom See editorial on page 1344. Background & Aims: It is widely recognized that genomic abnormalities underpin the development of human cancers. Aberrant patterns of chromosomal changes may represent useful information that can be used in classifying the complex traits of liver cancer cases for the genetic events involved in tumor carcinogenesis, tumor progression, and prognosis. Methods: Genome-wide chromosomal aberra- tions of 158 hepatitis B virus–associated hepatocellular car- cinoma (HCC) were studied by comparative genomic hybrid- ization (CGH). By application of a self-organizing tree algorithm, statistically significant CGH events were used to construct an evolutionary tree that could infer patient sub- groups with different degrees of tumor progression. The key CGH events in the subgroups were identified. The clinical significance of the groupings and the key CGH events were examined. Results: Based on the patterns of significant chromosomal aberrations derived, 3 HCC subgroups orga- nized in an evolutionary tree were identified. The groupings possessed information reflecting the degrees of tumor pro- gression, including numbers of chromosomal aberrations, tumor stages, tumor sizes, and disease outcome. Gains of 1q21-23 and 8q22-24 were identified as genomic events as- sociated with the early development of HCC. Gain of 3q22- 24, however, was identified as 1 of the late genomic events found to be associated with tumor recurrence and poor overall patient survival. Conclusions: A tumor progres- sion model for HCC was constructed and revealed chromo- somal imbalances that were significantly associated with clinical pathologic characteristics of the disease. This model explains a significant part of the variations in clinical out- come among HCC patients. G enomic abnormalities play important roles in carcinogen- esis. Identification of key genomic events causing cancer development and tumor progression not only helps understand cancer biology, but also may have direct clinical value. Over the last 40 years, the importance of chromosome aberrations in pathogenesis of cancer has been widely recognized. 1 In cancer cells, some chromosomes are broken and translocated to other chromosomes, some are deleted, some are truncated, and some are amplified. Some abnormalities are tumor specific, whereas some happen randomly. Specific chromosomal aberration re- sults in the suppression of the expression of the cancer sup- pressor genes or amplification of the proto-oncogenes or onco- genes. Because genes are located in the chromosomes in a specific order, the positions of the genes may influence the chromosomal aberration process during carcinogenesis. Fur- thermore, the chromosome aberrations may happen in a spe- cific order. 2 For example, deletion of chromosome 3p may happen before the amplification of chromosome 8q. A common hypothesis is that specific patterns of chromosomal aberrations and gene expression are present in different subtypes of liver cancers. Comparative genomic hybridization (CGH) is a labo- ratory technique allowing global assessment of copy number of changes of chromosomes, and indicating the chromosome re- gions that are either gained or lost in a tumor sample. Hepatocellular carcinoma (HCC) is the major primary liver malignancy that carries a high mortality and dismal prognosis. Although the prevalence demonstrates a preferential geo- graphic distribution in China, Southeast Asia, and Sub-Saharan Africa, a rising incidence of HCC in the United States and parts of Europe has been observed in recent years. 3,4 Epidemiologic studies have indicated that the development of HCC is strongly associated with viral hepatitis infections, the main etiologic factor being chronic hepatitis B virus (HBV) infection, to which 50% of the cases are attributable worldwide. 5 Like other solid tumors, HCC is considered to develop through successive ad- ditions of genetic alterations in tissues exposed to carcinogens. Although the causative links and common genomic aberrations associated are now well-recognized, the molecular events by which specific genomic alterations drive the pathogenesis are still not well understood. Abbreviations used in this paper: AJCC, American Joint Commission on Cancer; CGH, comparative genomic hybridization; DIG, digoxigenin; EIM, expression imbalance map; HCC, hepatocellular carcinoma; LOH, loss of heterozygosity; SOTA, self-organizing tree algorithm. © 2006 by the American Gastroenterological Association (AGA) Institute 0016-5085/06/$32.00 doi:10.1053/j.gastro.2006.08.014 GASTROENTEROLOGY 2006;131:1262–1270