Role of p53 and β-catenin mutations in conjunction with CK19 expression on early tumor recurrence and prognosis of hepatocellular carcinoma.
BACKGROUND
Cytokeratin 19 (CK19), a molecular marker of hepatic progenitor cells and cholangiocytes, is expressed in hepatocellular carcinomas (HCC), but not in normal hepatocytes. However, role of CK19 in HCC progression, especially when interacted with p53 and β-catenin mutations, remained largely unknown.


METHODS
From January 1983 to December 1997, 210 surgically resected, unifocal, primary HCCs were studied retrospectively. CK19 protein expression was detected by immunohistochemistry while mutations of p53 and β-catenin genes were detected by direct DNA sequencing.


RESULTS
CK19 protein expression was detected in 35.7% (75/210), p53 mutation in 47.2% (83/176) and β-catenin mutation in 14.5% (27/186). The tumor size (p=0.0023), grade (p  = 0.00093), tumor stage (p  = 4  x  10-7), high α-fetoprotein (p=0.0004), p53 mutation (p  = 0.024), absence of β-catenin mutation (p  =  0.0013), and CK19 expression (p  =  3 x 10-5) were markers predictive of early tumor recurrence (ETR). CK19 expression, stage, and ETR were strong indicators of poor prognosis (all p  <  0.0001). Importantly, combination analysis showed an additive unfavorable prognostic interaction of CK19 expression and p53 mutation. On the contrary, concurrent CK19 expression and β-catenin mutation was rare and CK19 expression abolished the suppression effect of β-catenin mutation on HCC progression.


CONCLUSIONS
CK19 expression is associated with more aggressive HCC. CK19 cooperates with p53 mutation towards advanced disease. In contrast, CK19 expression and β-catenin mutation play dramatic opposite roles in vascular invasion, ETR and the prognosis of HCC.
Department of Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10051, Taiwan.
Ray-Hwang
RH
Yuan
Yung-Ming
YM
Jeng
Rey-Heng
RH
Hu
Po-Lin
PL
Lai
Po-Huang
PH
Lee
Chia-Chi
CC
Cheng
Hey-Chi
HC
Hsu
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D005260:Female; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D053539:Keratin-19 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D015996:Survival Rate; D013997:Time Factors; D055815:Young Adult; D000509:alpha-Fetoproteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D015415:Biomarkers; D053539:Keratin-19; D000509:alpha-Fetoproteins; D051176:beta Catenin