Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis.
OBJECTIVE
To evaluate how characterization of genetic alterations can help in the elucidation of liver carcinogenesis pathways, 137 tumors were analyzed.


METHODS
High-density allelotype, p53, Axin1, and beta-catenin gene mutations were determined. Alterations were analyzed according to clinical parameters.


RESULTS
Tumors could be divided into 2 groups according to chromosome stability status. In the first group, demonstrating a chromosome stability, beta-catenin mutation associated with chromosome 8p losses were frequently found as the single genetic alterations. beta-catenin mutations were associated with large tumor size and with negative hepatitis B virus status. In the second group, demonstrating a chromosome instability, the most frequent allelic losses were on chromosome 1p, 4q, 6q, 9p, 13q, 16p, 16q, and 17p; Axin1 and p53 were frequently mutated. All of these alterations, except losses on 6q and 9p, were associated with hepatitis B virus infection. P53 mutations, 17p, 13q losses, and a high value of the fractional allelic loss index were associated with poor differentiated tumors, independently of risk factors. Finally, in the whole series, chromosome 9p and 6q losses were associated with poor prognosis.


CONCLUSIONS
Two main pathways defined by genetic alterations show different risk factors and clinical characteristics. Furthermore, loss of chromosome 9p or 6q is an independent prognostic indicator.
Laurent-Puig
P
P
INSERM U434, CEPH, Paris; Assistance Publique Hôpitaux de Paris, France.
Legoix
P
P
Bluteau
O
O
Belghiti
J
J
Franco
D
D
Binot
F
F
Monges
G
G
Thomas
G
G
Bioulac-Sage
P
P
Zucman-Rossi
J
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060466:Axin Protein; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D003598:Cytoskeletal Proteins / Q000235:genetics; D005260:Female; D016158:Genes, p53; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011506:Proteins / Q000235:genetics; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin
C555451:AXIN1 protein, human; D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D011506:Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin