Hypermethylation of the p16 gene and lack of p16 expression in hepatoblastoma.
Hepatoblastoma is the most frequent pediatric liver tumor that develops mostly in young children. Abnormal regulation of cell cycle regulatory genes including p16 has been described, displaying no p16 mRNA and p16 protein in hepatoblastomas. The inactivation of p16, leading to the disruption of cell cycle control is involved in many types of human malignancies. However, the mechanism of the p16 inactivation in hepatoblastomas has not yet been elucidated. In this present study, we examined the methylation status of the p16 gene promoter by using methylation-specific PCR in 24 cases of hepatoblastomas and in 20 cases of corresponding non-neoplastic liver tissue. Aberrant methylation of 5' CpG islands of p16 was present in 12 of 24 (50.0%) cases of hepatoblastoma. Clinicopathologic parameters were not associated with the methylation status of p16. To correlate the methylation status of p16 with the expression of p16, immunohistochemical staining was done in tumors and non-neoplastic liver tissue. All non-neoplastic liver tissues displayed moderate, but heterogeneous immunoreactivity for p16. Eight of 12 (66.6%) methylation-positive hepatoblastomas showed a complete lack of immunoreactivity for p16. The other 4 methylation-positive hepatoblastomas had heterogeneous immunoreactivity. Nine of 12 (75.0%) unmethylated cases of hepatoblastoma displayed diffuse immunoreactivity, whereas 3 cases of unmethylated hepatoblastoma were not immunostained for p16. Our data indicate that the hypermethylation of p16 is a major mechanism of the transcriptional repression of p16 in hepatoblastomas, and we suggest that the inactivation of p16, leading to the lack of p16, may play an important role in the tumorigenesis of hepatoblastomas.
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Korea.
Yhong-Hee
YH
Shim
Hye-Jung
HJ
Park
Mi Sun
MS
Choi
Jung Sun
JS
Kim
Hanseoung
H
Kim
Jong Jae
JJ
Kim
Ja-June
JJ
Jang
Eunsil
E
Yu
D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D019942:Genes, p16; D018197:Hepatoblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm