Intratumoral genomic heterogeneity in human hepatocellular carcinoma detected by restriction landmark genomic scanning

Background/Aims: One of the unique features of advanced hepatocellular carcinoma (HCC) is the morphological heterogeneity in a single tumor nodule. In order to investigate the intratumoral genomic heterogeneity of HCC, we performed Restriction Landmark Genomic Scanning (RLGS), which allows genomic DNAs to be surveyed at approximately 2000 landmark sites in a single 2-dimensional gel electrophoresis. Methods: RLGS profiles of two regions from a single HCC nodule in six patients were compared with nontumorous liver tissue. Four HCCs consisting of moderately-differentiated cells were separated into several small parts by thin fibrous septa, but not encapsulated. DNA samples were obtained from both parts of these so-called “nodule-in-nodule” HCC. Two HCCs consisting of well-differentiated cells which did not have a definite partition appeared pathologically homogeneous, and two independent regions of the HCC were used for the analysis. Results: All six HCCs demonstrated different RLGS profiles (in total about 160 different spots) from the corresponding non-tumorous liver, and the number of different spots was greater in the 4 moderately-differentiated nodule-in-nodule HCCs (39–68 spots) than in the 2 well-differentiated homogeneous HCCs (6 and 3 spots). RLGS profiles of the two parts were different to each other in all 4 nodule-in-nodule HCCs. On the other hand, two other homogeneous HCCs showed the same RLGS profiles in the two regions. Conclusion: Thus, intratumoral genomic heterogeneity was demonstrated in the advanced HCC samples, and the genomic alterations may relate to the progression of HCC.