ABSTRACT
Hepatocellular carcinoma (HCC) is linked etiologically to viruses (hepatitis B virus
[HBV] and hepatitis C virus [HCV]), chemical carcinogens (i.e., aflatoxins), and other
environmental and host factors causing chronic liver injury. Some hepatoblastomas
may be linked to inherited gene mutations, but adult hereditary HCC appears to be
rare. HCCs display gross genomic alterations, including DNA rearrangements associated
with HBV DNA integration, loss of heterozygosity, and, less importantly, chromosomal
amplifications and loss of imprinting. Many genes with somatic mutations have now
been identified in these tumors. Most frequently involved genes are tumor suppressor
genes such as p53, M6P/IGF2R, β-catenin, p16INK4A, and retinoblastoma genes. Most
identified mutations are somatic, but germline mutations of p16INK4A, APC, and BRCA2
have also been reported. Oncogenic activation of several cellular genes such as cyclin
D and cyclin A have been described in HCC, but the possible implication of candidate
viral oncogenes (i.e., X protein of HBV) is still debated. A comprehensive analysis
of all the genetic changes described for HCC demonstrates that at least four different
growth regulatory pathways are altered in these tumors. However, each pathway appears
to be implicated in a limited fraction of these tumors, suggesting that HCCs are genetically
heterogenous neoplasms. This genetic heterogeneity correlates with the heterogeneity
of etiologic factors implicated in HCC.
KEY WORDS
hepatocellular carcinoma - primary liver cancer - p53 - p16INK4A - cyclin D - β-catenin
- M6P/IGF2R
