Is p53 gene mutation an indicatior of the biological behaviors of recurrence of hepatocellular carcinoma?
OBJECTIVE
To evaluate mutant p53 gene in primary hepatocellular carcinoma and to investigate the correlation between it and the recurrence of hepatocellular carcinoma.


METHODS
Mutations of p53 gene were examined using anti-human p53 monoclonal antibody and immunohistochemical staining in 79 resected hepatocellular carcinomas. The correlations among variables of p53 positivity and invasiveness, disease free interval and survival were studied. In addition, in those who developed recurrence, the correlation among p53 positivity, clinical features and post-recurrence survival were also studied.


RESULTS
Of these 79 cases, 64 (81 %) had p53 mutation. Those patients with mutant p53 positivity had significantly more tumor recurrence (76.6 % vs 40.0 %, P=0.0107). However, the COX proportional hazards model showed that p53 overexpression had only weak correlations with recurrence free interval and survival time (P=0.088 and 0.081), which was probably related to the short duration of follow-up. The invasiveness variables may be predictors of HCC recurrence. On univariate analysis, more patients with mutant p53 positivity had vascular permeation (78.1 vs 40.0 %, P=0.0088, O.R. (odds ratio) =5.3), grade II-IV differentiation (98.4 vs 80.0 %, P=0.0203, O.R. =15.7), no complete capsule (82.8 vs 53.3 %, P=0.0346, O.R. =4.2) and daughter nodules (60.9 vs. 33.3 %, P=0.0527, O.R. =3.1) than patients with negative p53 staining. On multivariate analysis, only vascular permeation and grade of differentiation remained significant (P=0.042 and 0.012). There was no statistically significant correlation between the status of p53 in the primary lesion and the clinical features of recurrent hepatocellular carcinomas examined, including extrahepatic metastasis (P=0.1103) and the number of recurrent tumors (P=1.000) except for disease over more than one segment in the extent of recurrent tumors (P=0.0043). The post-recurrence median survival was lower in patients in whom p53 mutation had been detected in the primary lesion with a weak significance (3.42 months vs 11.0 months, P=0.051).


CONCLUSIONS
Our findings suggest that p53 mutation correlates significantly with invasiveness including vascular permeation, grade of cellular differentiation, incomplete capsule and multinodular lesions. Hepatocellular carcinomas with p53 mutations had more tumor recurrence and p53 mutation may also influence disease recurrence interval and survival time. Hepatocellular carcinomas with p53 mutations recur more extensively with a shorter survival. Therefore, p53 mutation in the primary lesion is useful as an indicator of the biological behavior of recurrent hepatocellular carcinomas.
Sheen
I-Shyan
IS
Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan.
Jeng
Kuo-Shyang
KS
Wu
Ju-Yann
JY
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D005260:Female; D016158:Genes, p53; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000503:physiopathology