P14ARF gene alterations in human hepatocellular carcinoma.
BACKGROUND
The molecular status of the p14(ARF) gene has not been fully elucidated in hepatocellular carcinoma (HCC). This study was performed to determine genetic and epigenetic alterations in the p14(ARF) tumor suppressor gene and their effect on HCC progression.


METHODS
The status of p14 was evaluated in 117 HCC tumoral nodules and 110 corresponding non-tumor tissues by loss of heterozygosity at the 9p21-22 region, homozygous deletions, single strand conformation polymorphism-polymerase chain reaction mutational analysis and methylation-specific polymerase chain reaction.


RESULTS
The most frequent inactivation mechanism was hypermethylation of the promoter region, which was found in 41.9% of tumor samples and in 19.1% of non-tumor samples. Loss of heterozygosity at the 9p21 region was detected in 27.3% and 10% of tumor and non-tumor tissues, respectively. Homozygous deletions and mutations were less common events in hepatocarcinogenesis. We found 5.9% of the tumor cases with exon 2 homozygous deletions and 3.4% of the cases with mutations. We described a silent mutation in codon 42 of exon 1beta for the first time. No association was found between inactivation of p14(ARF) and clinicopathological characteristics or prognosis.


CONCLUSIONS
We can conclude that p14(ARF) is frequently and early altered in HCC, being the main cause of inactivation promoter hypermethylation. Our results suggest that the p14(ARF) gene plays an important role in the pathogenesis of hepatocellular carcinoma.
Anzola
Monica
M
Departamento de Z. y Dinámica Celular, Facultad de Farmacia, Universidad del Pais Vasco, Vitoria, Spain.
Cuevas
Nerea
N
López-Martínez
Monica
M
Saiz
Alberto
A
Burgos
Juan José
JJ
Martínez de Pancorboa
Marian
M
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics; D016019:Survival Analysis; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
D025803:Tumor Suppressor Protein p14ARF