Genomic aberrations in human hepatocellular carcinomas of differing etiologies

We sought to assess whether genetic abnormalities in hepatocellular carcino ma differed in geographic locations associated with different risk factors. Comparative genomic hybridization (CGH) was applied to the genome-wide chr omosomal analysis in 83 tumor samples from four different geographic origin s. Samples were obtained from regions that differed in aflatoxin exposure: China (Hong Kong with low aflatoxin exposure and Shanghai with moderate afl atoxin exposure), Japan, and the United States (negligible aflatoxin exposu re). Cases from Hong Kong and Shanghai were all hepatitis B virus (HBV) rel ated, those from Japan were hepatitis C virus related, and those from the U nited States were HBV negative. In parallel, the mutational pattern of the whole p53 gene (exons 1-11) was also investigated in these cases, CGH revea led a complex pattern of chromosomal gains and losses, with the commonest a berration in each geographic location being chromosome Iq copy number gain (38-60%), Shanghai cases displayed the highest number of total aberrations per sample,,vith significant copy losses on 4q (75%), 8p (70%), and 16q (65 %). Hepatitis C virus-related samples from Japan had a characteristically h igh incidence of 11q13 gain. p53 mutation(s) was detected in 23% of Hong Ko ng cases, 40% of Shanghai, 31% of Japan, hut only 6% of the United States c ases. The "aflatoxin-associated" codon 249 mutation was, however, identifie d only in samples from China (13% Hang Kong and 20% Shanghai), This finding , together with the highly aberrant pattern of genetic changes detected in the Shanghai series, is suggestive of the genotoxic effects of anatoxin bei ng more broadly based. It is also likely that there is a synergistic effect of HBV infection and high aflatoxin exposure in promoting hepatocellular c arcinoma development. It appears from our CGH study that individual risk fa ctors are indeed associated with distinct genetic aberrations, although cha nges in Iq gain appear common to all.