CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma.
Biliary intraepithelial neoplasia (BilIN) is the premalignant lesion of extrahepatic cholangiocarcinoma (EHC), and there are no published data regarding epigenetic changes throughout disease progression from normal biliary epithelia to BilIN to EHC. The objective of this study was to identify the occurrence of CpG island hypermethylation and repetitive DNA hypomethylation in BilIN. A total of 50 EHCs, 31 BilINs, and 31 normal cystic duct samples were analyzed for their methylation status in seven genes and two repetitive DNA elements. The number of methylated genes increased with disease progression (normal bile duct, 0.6; BilIN, 2.0; EHC, 3.6; P < 0.001). The methylation level of examined genes was significantly higher in BilIN than in normal samples (TMEFF2, HOXA1, NEUROG1, and RUNX3, P < 0.05) and in EHC than in BilIN samples (TMEFF2, HOXA1, NEUROG1, RUNX3, RASSF1A, and APC, P < 0.05). Long interspersed nucleotide element-1 (LINE-1) and juxtacentromeric satellite 2 (SAT2) methylation levels were markedly lower in EHC than in normal duct and BilIN samples, and BilIN samples showed a decrease of SAT2 methylation levels but no decrease of LINE-1 methylation levels compared to normal samples. These findings suggest that most of cancer-specific CpG island hypermethylation occur in the stage of BilIN and that CpG island hypermethylation seems to occur earlier than repetitive DNA element hypomethylation.
Kim
Baek-hui
BH
Department of Pathology, Korea University Medical School, Seoul, South Korea.
Cho
Nam-Yun
NY
Shin
So Hyun
SH
Kwon
Hyeong-Ju
HJ
Jang
Ja June
JJ
Kang
Gyeong Hoon
GH
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology; D017734:Bile Ducts, Extrahepatic; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D018398:Homeodomain Proteins / Q000235:genetics; D020084:Long Interspersed Nucleotide Elements; D008565:Membrane Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000099261:Homeobox A1 Protein
D051792:Basic Helix-Loop-Helix Proteins; D050677:Core Binding Factor Alpha 3 Subunit; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099261:Homeobox A1 Protein; C105389:NEUROG1 protein, human; C411762:RASSF1 protein, human; C493729:Runx3 protein, human; C423567:TMEFF2 protein, human