Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma.
IGF2, a maternally imprinted foetal growth factor gene, is implicated in many childhood tumours including hepatoblastoma (HB); however, the genetic and epigenetic alterations have not comprehensively been studied. We analysed the methylation status of the H19 differentially methylated region (DMR), loss of heterozygosity (LOH) and allelic expression of IGF2 in 54 HB tumours, and found that 12 tumours (22%) with LOH, 9 (17%) with loss of imprinting (LOI) and 33 (61%) with retention of imprinting (ROI). Biallelic and monoallelic IGF2 expressions correlated with hypermethylation and normal methylation of H19 DMR, respectively, in two tumours with LOI and seven tumours with ROI. Quantitative RT-PCR analysis showed minimal expression of H19 mRNA and substantial expression of IGF2 mRNA in tumours with LOH or LOI, and substantial expression of both H19 and IGF2 mRNAs in tumours with ROI. Increased IGF2 expression with predominant embryonic P3 transcript was found in the majority of HBs with ROI and foetal livers. In contrast to the earlier reports, our findings suggest that the disruption of the enhancer competition model reported in Wilms' tumour may also occur in HB. Both frequencies of LOH and LOI seem to be lower in HB than in Wilms' tumour, reflecting the different tissue origins.
Honda
S
S
Department of Cancer Diagnosis, Saitama Cancer Center, Research Institute for Clinical Oncology, 818 Komuro, Ina, Saitama 362-0806, Japan.
Arai
Y
Y
Haruta
M
M
Sasaki
F
F
Ohira
M
M
Yamaoka
H
H
Horie
H
H
Nakagawara
A
A
Hiyama
E
E
Todo
S
S
Kaneko
Y
Y
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D018392:Genomic Imprinting; D018197:Hepatoblastoma / Q000235:genetics*; D006801:Humans; D007223:Infant; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051176:beta Catenin / Q000235:genetics
C495270:CTNNB1 protein, human; D004268:DNA-Binding Proteins; C035170:IGF2 protein, human; C104382:PLAG1 protein, human; D012333:RNA, Messenger; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II