Micronuclei and broken eggs in human liver carcinogenesis

BACKGROUND: Micronuclei (MNi) and broken eggs (BE) are both considered sensitive markers of genotoxic damage and chromosomal instability. In humans, a high frequency of MNi is reported in both cirrhosis and hepatocellular carcinoma, but no information is available on MNi/BE expression in dysplastic nodules. MNi/BE formation may result in activation of the p53-mediated cell cycle checkpoint. MATERIALS AND METHODS: MNi, BE (Feulgen staining) and immunohistochemical expression of p53 and Mib1 were assessed in 95 liver lesions representing the whole spectrum of liver carcinogenesis. Seven normal liver tissue samples served as controls. MNi and BE were assessed by video-assisted microscopy and expressed as a crude number per 1,000 hepatocytes. RESULTS: MNi and BE were significantly more frequent in all the pathological samples than in the controls (p<0.001). A progressively increasing number of MNi/BEs was documented from cirrhotic nodules (CN) to large regenerative nodules (LRN), to dysplastic nodules (DN) and hepatocellular carcinoma (HCC) (test for trend; p<0.001). MNi were significantly more frequent in DN than in CN or LRN (p=0.011; p=0.020, respectively). Proliferative activity (Mib1) and p53 expression were significantly associated with MNi presence (p<0.001 and p=0.031, respectively). CONCLUSION: Chromosomal instability significantly increases throughout the multistep course of hepatocarcinogenesis. The similar prevalence of MNi and BEs in DN and HCC supports their strict biological similarity. A high prevalence of MNi/BE may identify a subset of (genetically unstable) cancer-prone cirrhosis cases.