Characterization of Hepatocellular Carcinoma Patients with Amplification Assessed by Fluorescence in situ Hybridization: A Large Cohort Study.

BACKGROUND

amplification is a relatively novel type of genetic aberration that has been proposed to be a driver of hepatocarcinogenesis. Selective inhibitors of , a receptor of , have been developed as targeted therapies for hepatocellular carcinoma (HCC). Despite the role of in mediating HCC progression, the clinicopathological characterization of patients exhibiting amplification remains unclear. Immunohistochemical staining is the simplest and most widely used method of identifying aberrations in the gene, although its specificity is very low.

METHODS

This study investigated the prognostic significance of amplification in a large cohort of 989 HCC patients using fluorescence in situ hybridization (FISH), which has a high degree of specificity. In addition, FISH data from formalin-fixed, paraffin-embedded sections were compared with copy number variation (CNV) data obtained from fresh frozen sections to validate the use of FISH as a diagnostic tool.

RESULTS

amplifications were detected by FISH in 51 (5.15%) of the 989 patients, and were independently associated with poor survival and a higher risk of tumor recurrence, as well as with poor prognostic factors such as a high α-fetoprotein level, hepatitis B or C virus infection, a large tumor size, microvascular invasion, and necrosis. In addition, amplification was associated with mutation, and was mutually exclusive with mutation. The results of the FISH and CNV analyses exhibited a significant concordance rate of 96% (κ = 0.618, < 0.001).

CONCLUSIONS

These data indicate that amplification represents a unique molecular subtype associated with poor prognostic characteristics, which supports the hypothesis that the signaling pathway plays an important role in hepatocarcinogenesis. We have also demonstrated that FISH is a viable alternative to CNV analysis, offering a number of advantages in the clinical setting.