Hypomethylation of long interspersed nuclear element-1 in hepatocellular carcinomas.
Recent studies have revealed the epigenetic alterations are involved in hepatocarcinogenesis. However, the function of long interspersed nuclear element-1 hypomethylation in hepatocellular carcinomas, and relationship among other clinicopathologic features, and genetic and epigenetic alterations, including CpG island hypermethylation, have not been studied. We determined long interspersed nuclear element-1 methylation, a marker of global methylation, in 57 tumor and nonneoplastic samples, including 24 from high-risk and 33 from low-risk countries. We compared methylation levels of long interspersed nuclear element-1 with eight CpG islands including p16, cyclooxygenase-2, T-type calcium channel, and estrogen receptor genes, and MINT31, MINT1, MINT2, and MINT27, as well as CpG island methylator phenotype and p53 gene mutation. Most hepatocellular carcinomas samples (88%) showed hypomethylation of long interspersed nuclear element-1, with a mean level of global methylation of 58+/-14 compared to 77+/-6 in nonneoplastic hepatic tissue (P<0.001). Levels of long interspersed nuclear element-1 hypomethylation differed depending on geographic location (P=0.02), status of hepatitis (P=0.01), hypermethylation of p16, estrogen receptor and MINT2 (P=0.01, 0.002, and 0.045, respectively), CpG island methylator phenotype-positive status (P=0.006), and p53 gene mutation (P=0.04). In conclusion, environmental factors such as geographic location and hepatitis status contribute to hepatocarcinogenesis through global hypomethylation. In hepatocellular carcinomas, hypermethylation of CpG islands, and CpG island methylator phenotype status seems to correlate with levels of long interspersed nuclear element-1 hypomethylation.
Kim
Mi-Jung
MJ
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
White-Cross
Jill A
JA
Shen
Lanlan
L
Issa
Jean-Pierre J
JP
Rashid
Asif
A
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; C476510:SPEN protein, human; D016159:Tumor Suppressor Protein p53