Molecular biology of hepatocellular carcinoma


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Nathalie Wong

Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China

Abstract

Molecular biology of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly malignant tumour that is commonly fatal. Like other solid tumours, HCC is considered to develop through successive additions of genetic alterations. Various studies have reported on the chromosomal instability in HCC, where genetic abnormalities including rearrangements, allelic deletions, gene amplifications and mutations, as well as epigenetic alterations have been described. Despite much effort has been made to obtain a comprehensive picture on the genomic abnormalities presented, information on the molecular events that underscores the stepwise progression of HCC remained largely undefined. Bioinformatics offer new solutions to data analysis and permits the formulation of new hypothesis. In an effort to simulate a tumour progression model for HCC, we attempted unsupervised neural network analysis on the genome-wide aberrations of >150 HCC cases that were previously studied by the chromosome-based comparative genomic hybridization (CGH). By the application of a self-organizing tree algorithm, specific regional chromosomal gains and losses were suggested in association with the initiation and progression of HCC. Significant CGH events identified were further used to construct an evolutionary tree that held inference for patient subgroups at differing degrees of tumour progression. Based on the pattern of genomic aberrations obtained, gains of 1q21-q23 and 8q22-q24 were recognized as key events associated with early HCC development, whilst regional gains of such as 7q21-q31 and 3q22-q24 were considered late genomic changes involved in tumour advancements. Aberrant genomic loci identified can be further investigated for underlying tumour suppressors and oncogenes by various mapping tools these days. Examples from our group on the array-based mapping analysis in HCC will be presented. Our studies suggested that identification of specific chromosomal aberrations has been a useful first step towards delineating candidate gene(s) associated with the development and progression of HCC. Further downstream positional mapping by the array-based approach has proved useful in enabling the direct identification of affected genes within aberrant genomic loci.