CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma

• Published in: Virchows Archiv : an international journal of pathology Vol. 455; no. 4; pp. 343 - 351
• Main Authors: Kim, Baek-hui, Cho, Nam-Yun, Shin, So Hyun, Kwon, Hyeong-Ju, Jang, Ja June, Kang, Gyeong Hoon
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.10.2009; Springer; Springer Nature B.V
• Subjects: Basic Helix-Loop-Helix Transcription Factors - genetics; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - pathology; Bile Ducts, Extrahepatic; Biological and medical sciences; Cholangiocarcinoma - genetics; Cholangiocarcinoma - pathology; Core Binding Factor Alpha 3 Subunit - genetics; CpG Islands; Deoxyribonucleic acid; Disease Progression; DNA; DNA Methylation; Gastroenterology. Liver. Pancreas. Abdomen; Homeodomain Proteins - genetics; Investigative techniques, diagnostic techniques (general aspects); Lesions; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Long Interspersed Nucleotide Elements; Medical sciences; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Methylation; Neoplasm Proteins - genetics; Nerve Tissue Proteins - genetics; Original Article; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Precancerous Conditions - genetics; Transcription Factors - genetics; Tumor Suppressor Proteins - genetics; Tumors; Biliary intraepithelial neoplasia; DNA hypermethylation; CpG island; Cholangiocarcinoma; DNA hypomethylation; Biliary tract; Repetitive DNA; Premalignant lesion; Nucleotide sequence; Digestive system; Repeated sequence; Hepatic disease; Malignant tumor; Biliary tract disease; Anatomic pathology; GC rich sequence; Malignant cholangioma; Digestive diseases; Methylation; Intraepithelial neoplasia; Cancer
• ISSN: 0945-6317; 1432-2307
• DOI: 10.1007/s00428-009-0829-4

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.