Analysis of chromosomal instability in pulmonary or liver metastases and matched primary hepatocellular carcinoma after orthotopic liver transplantation.
To investigate the genetic mechanism of metastatic spread in hepatocellular carcinoma (HCC), we analyzed genomic changes in lung or liver metastases and the corresponding primary tumors (83 tumor samples) in 18 patients who underwent orthotopic liver transplantation. We studied the incidence of microsatellite instability (MSI) and loss of heterozygosity (LOH) involving 8 highly polymorphic microsatellite markers and the polyA tract, Bat26. We also sought alterations of p53 and beta-catenin gene mutations. High MSI (>30-40% of the loci analyzed) was found only in primary tumors (11%), whereas LOH was observed in 50% of primary and in 39% of recurrent tumors. p53 mutations were found in 2 cases of primary HCC but not in the corresponding metastases. P53 was overexpressed in 4 primary HCC (22%) and 7 metastases (39%). The percentage of beta-catenin gene mutations was low (6%). Lung metastases retained the D16S402 microsatellite abnormalities observed in the primary tumors, whereas recurrent liver tumor did not (p = 0.02). In conclusion, LOH and P53 protein overexpression, rather than mutations in the p53 or beta-catenin genes or MSI, seem to be involved in the spreading of HCC, suggesting the presence of metastasis suppressor genes in the vicinity of the chromosomal loci in question.
Gross-Goupil
Marine
M
Service de Biochimie et Biologie moléculaire, Hôspital Universitaire Paul Brousse, INSERM U268, IFR 89 "Biologie intégrée de la cellule, Birus et Cancer," Faculté de Médicine Paris-Sud, Paris, France.
Riou
Philippe
P
Emile
Jean-François
JF
Saffroy
Raphaël
R
Azoulay
Daniel
D
Lacherade
Isabelle
I
Receveur
Aline
A
Piatier-Tonneau
Dominique
D
Castaing
Denis
D
Debuire
Brigitte
B
Lemoine
Antoinette
A
D000293:Adolescent; D000328:Adult; D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000556:secondary / Q000601:surgery / Q000821:virology; D002875:Chromosomes / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D016174:Hepacivirus / Q000472:pathogenicity; D006509:Hepatitis B / Q000378:metabolism / Q000473:pathology; D006515:Hepatitis B virus / Q000472:pathogenicity; D006526:Hepatitis C / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery / Q000821:virology; D016031:Liver Transplantation; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary / Q000821:virology; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin