Skip to main content
Erschienen in: Virchows Archiv 4/2009

01.10.2009 | Original Article

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

verfasst von: Baek-hui Kim, Nam-Yun Cho, So Hyun Shin, Hyeong-Ju Kwon, Ja June Jang, Gyeong Hoon Kang

Erschienen in: Virchows Archiv | Ausgabe 4/2009

Einloggen, um Zugang zu erhalten

Abstract

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.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Fleming KA, Boberg KM, Glaumann H et al (2001) Biliary dysplasia as a marker of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 34:360–365CrossRefPubMed Fleming KA, Boberg KM, Glaumann H et al (2001) Biliary dysplasia as a marker of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 34:360–365CrossRefPubMed
2.
Zurück zum Zitat Laitio M (1983) Carcinoma of extrahepatic bile ducts. A histopathologic study. Pathol Res Pract 178:67–72PubMed Laitio M (1983) Carcinoma of extrahepatic bile ducts. A histopathologic study. Pathol Res Pract 178:67–72PubMed
3.
Zurück zum Zitat Kim JPY, Kim H (1998) Immunohistochemical characteristics of biliary tract carcinoma and its precancerous lesions. Korean J Pathol 32:985–992 Kim JPY, Kim H (1998) Immunohistochemical characteristics of biliary tract carcinoma and its precancerous lesions. Korean J Pathol 32:985–992
4.
Zurück zum Zitat Suzuki M, Takahashi T, Ouchi K et al (1989) The development and extension of hepatohilar bile duct carcinoma. A three-dimensional tumor mapping in the intrahepatic biliary tree visualized with the aid of a graphics computer system. Cancer 64:658–666CrossRefPubMed Suzuki M, Takahashi T, Ouchi K et al (1989) The development and extension of hepatohilar bile duct carcinoma. A three-dimensional tumor mapping in the intrahepatic biliary tree visualized with the aid of a graphics computer system. Cancer 64:658–666CrossRefPubMed
5.
Zurück zum Zitat Zen Y, Adsay NV, Bardadin K et al (2007) Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol 20:701–709CrossRefPubMed Zen Y, Adsay NV, Bardadin K et al (2007) Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol 20:701–709CrossRefPubMed
6.
Zurück zum Zitat Scarpa A, Zamboni G, Achille A et al (1994) ras-family gene mutations in neoplasia of the ampulla of Vater. Int J Cancer 59:39–42CrossRefPubMed Scarpa A, Zamboni G, Achille A et al (1994) ras-family gene mutations in neoplasia of the ampulla of Vater. Int J Cancer 59:39–42CrossRefPubMed
7.
Zurück zum Zitat Suto T, Habano W, Sugai T et al (2000) Aberrations of the K-ras, p53, and APC genes in extrahepatic bile duct cancer. J Surg Oncol 73:158–163CrossRefPubMed Suto T, Habano W, Sugai T et al (2000) Aberrations of the K-ras, p53, and APC genes in extrahepatic bile duct cancer. J Surg Oncol 73:158–163CrossRefPubMed
8.
Zurück zum Zitat Nakanishi Y, Zen Y, Kondo S et al (2008) Expression of cell cycle-related molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm. Hum Pathol 39:1153–1161CrossRefPubMed Nakanishi Y, Zen Y, Kondo S et al (2008) Expression of cell cycle-related molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm. Hum Pathol 39:1153–1161CrossRefPubMed
9.
Zurück zum Zitat Sasaki M, Yamaguchi J, Itatsu K et al (2008) Over-expression of polycomb group protein EZH2 relates to decreased expression of p16 INK4a in cholangiocarcinogenesis in hepatolithiasis. J Pathol 215:175–183CrossRefPubMed Sasaki M, Yamaguchi J, Itatsu K et al (2008) Over-expression of polycomb group protein EZH2 relates to decreased expression of p16 INK4a in cholangiocarcinogenesis in hepatolithiasis. J Pathol 215:175–183CrossRefPubMed
10.
Zurück zum Zitat Zen Y, Aishima S, Ajioka Y et al (2005) Proposal of histological criteria for intraepithelial atypical/proliferative biliary epithelial lesions of the bile duct in hepatolithiasis with respect to cholangiocarcinoma: preliminary report based on interobserver agreement. Pathol Int 55:180–188CrossRefPubMed Zen Y, Aishima S, Ajioka Y et al (2005) Proposal of histological criteria for intraepithelial atypical/proliferative biliary epithelial lesions of the bile duct in hepatolithiasis with respect to cholangiocarcinoma: preliminary report based on interobserver agreement. Pathol Int 55:180–188CrossRefPubMed
11.
Zurück zum Zitat Tsuneyama K, Sasaki M, Shimonishi T et al (2004) Expression of MAGE-A3 in intrahepatic cholangiocarcinoma and its precursor lesions. Pathol Int 54:181–186CrossRefPubMed Tsuneyama K, Sasaki M, Shimonishi T et al (2004) Expression of MAGE-A3 in intrahepatic cholangiocarcinoma and its precursor lesions. Pathol Int 54:181–186CrossRefPubMed
12.
Zurück zum Zitat Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168–174CrossRefPubMed Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168–174CrossRefPubMed
13.
Zurück zum Zitat Esteller M, Corn PG, Baylin SB et al (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229PubMed Esteller M, Corn PG, Baylin SB et al (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229PubMed
14.
Zurück zum Zitat Gaudet F, Hodgson JG, Eden A et al (2003) Induction of tumors in mice by genomic hypomethylation. Science 300:489–492CrossRefPubMed Gaudet F, Hodgson JG, Eden A et al (2003) Induction of tumors in mice by genomic hypomethylation. Science 300:489–492CrossRefPubMed
15.
Zurück zum Zitat Ogino S, Kawasaki T, Nosho K et al (2008) LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Int J Cancer 122:2767–2773CrossRefPubMed Ogino S, Kawasaki T, Nosho K et al (2008) LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Int J Cancer 122:2767–2773CrossRefPubMed
16.
Zurück zum Zitat Weisenberger DJ, Campan M, Long TI et al (2005) Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 33:6823–6836CrossRefPubMed Weisenberger DJ, Campan M, Long TI et al (2005) Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 33:6823–6836CrossRefPubMed
17.
Zurück zum Zitat Isaacs WB, Bova GS, Morton RA et al (1994) Molecular biology of prostate cancer. Semin Oncol 21:514–521PubMed Isaacs WB, Bova GS, Morton RA et al (1994) Molecular biology of prostate cancer. Semin Oncol 21:514–521PubMed
18.
Zurück zum Zitat Hake SB, Xiao A, Allis CD (2004) Linking the epigenetic ‘language’ of covalent histone modifications to cancer. Br J Cancer 90:761–769CrossRefPubMed Hake SB, Xiao A, Allis CD (2004) Linking the epigenetic ‘language’ of covalent histone modifications to cancer. Br J Cancer 90:761–769CrossRefPubMed
19.
Zurück zum Zitat Lee S, Lee HJ, Kim JH et al (2003) Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 163:1371–1378PubMed Lee S, Lee HJ, Kim JH et al (2003) Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 163:1371–1378PubMed
20.
Zurück zum Zitat Cho NY, Kim JH, Moon KC et al (2009) Genomic hypomethylation and CpG island hypermethylation in prostatic intraepithelial neoplasm. Virchows Arch 454:17–23CrossRefPubMed Cho NY, Kim JH, Moon KC et al (2009) Genomic hypomethylation and CpG island hypermethylation in prostatic intraepithelial neoplasm. Virchows Arch 454:17–23CrossRefPubMed
21.
Zurück zum Zitat Kim BH, Cho NY, Choi M et al (2007) Methylation profiles of multiple CpG island loci in extrahepatic cholangiocarcinoma versus those of intrahepatic cholangiocarcinomas. Arch Pathol Lab Med 131:923–930PubMed Kim BH, Cho NY, Choi M et al (2007) Methylation profiles of multiple CpG island loci in extrahepatic cholangiocarcinoma versus those of intrahepatic cholangiocarcinomas. Arch Pathol Lab Med 131:923–930PubMed
22.
Zurück zum Zitat Greene FL, American Joint Committee on Cancer, American Cancer Society (2002) AJCC cancer staging manual, 6th edn. Springer, New York Greene FL, American Joint Committee on Cancer, American Cancer Society (2002) AJCC cancer staging manual, 6th edn. Springer, New York
23.
Zurück zum Zitat Aaltonen LA, Hamilton SR, World Health Organization, International Agency for Research on Cancer (2000) Pathology and genetics of tumours of the digestive system. IARC, Lyon Aaltonen LA, Hamilton SR, World Health Organization, International Agency for Research on Cancer (2000) Pathology and genetics of tumours of the digestive system. IARC, Lyon
24.
Zurück zum Zitat Ogino S, Kawasaki T, Brahmandam M et al (2006) Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis. J Mol Diagn 8:209–217CrossRefPubMed Ogino S, Kawasaki T, Brahmandam M et al (2006) Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis. J Mol Diagn 8:209–217CrossRefPubMed
25.
Zurück zum Zitat Chalitchagorn K, Shuangshoti S, Hourpai N et al (2004) Distinctive pattern of LINE-1 methylation level in normal tissues and the association with carcinogenesis. Oncogene 23:8841–8846CrossRefPubMed Chalitchagorn K, Shuangshoti S, Hourpai N et al (2004) Distinctive pattern of LINE-1 methylation level in normal tissues and the association with carcinogenesis. Oncogene 23:8841–8846CrossRefPubMed
26.
Zurück zum Zitat Eads CA, Danenberg KD, Kawakami K et al (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28:E32CrossRefPubMed Eads CA, Danenberg KD, Kawakami K et al (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28:E32CrossRefPubMed
27.
Zurück zum Zitat Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428CrossRefPubMed Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428CrossRefPubMed
28.
Zurück zum Zitat Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89–92CrossRefPubMed Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89–92CrossRefPubMed
29.
Zurück zum Zitat Gama-Sosa MA, Slagel VA, Trewyn RW et al (1983) The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res 11:6883–6894CrossRefPubMed Gama-Sosa MA, Slagel VA, Trewyn RW et al (1983) The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res 11:6883–6894CrossRefPubMed
30.
Zurück zum Zitat Lee S, Hwang KS, Lee HJ et al (2004) Aberrant CpG island hypermethylation of multiple genes in colorectal neoplasia. Lab Invest 84:884–893CrossRefPubMed Lee S, Hwang KS, Lee HJ et al (2004) Aberrant CpG island hypermethylation of multiple genes in colorectal neoplasia. Lab Invest 84:884–893CrossRefPubMed
31.
Zurück zum Zitat Kang GH, Lee S, Kim JS et al (2003) Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis. Lab Invest 83:635–641PubMed Kang GH, Lee S, Kim JS et al (2003) Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis. Lab Invest 83:635–641PubMed
32.
Zurück zum Zitat Sato N, Fukushima N, Hruban RH et al (2008) CpG island methylation profile of pancreatic intraepithelial neoplasia. Mod Pathol 21:238–244CrossRefPubMed Sato N, Fukushima N, Hruban RH et al (2008) CpG island methylation profile of pancreatic intraepithelial neoplasia. Mod Pathol 21:238–244CrossRefPubMed
33.
Zurück zum Zitat Yamanaka M, Watanabe M, Yamada Y et al (2003) Altered methylation of multiple genes in carcinogenesis of the prostate. Int J Cancer 106:382–387CrossRefPubMed Yamanaka M, Watanabe M, Yamada Y et al (2003) Altered methylation of multiple genes in carcinogenesis of the prostate. Int J Cancer 106:382–387CrossRefPubMed
34.
Zurück zum Zitat Lee HS, Kim BH, Cho NY et al (2009) Prognostic implications of and relationship between CpG island hypermethylation and repetitive DNA hypomethylation in hepatocellular carcinoma. Clin Cancer Res 15:812–820CrossRefPubMed Lee HS, Kim BH, Cho NY et al (2009) Prognostic implications of and relationship between CpG island hypermethylation and repetitive DNA hypomethylation in hepatocellular carcinoma. Clin Cancer Res 15:812–820CrossRefPubMed
35.
Zurück zum Zitat Herman JG, Graff JR, Myohanen S et al (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93:9821–9826CrossRefPubMed Herman JG, Graff JR, Myohanen S et al (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93:9821–9826CrossRefPubMed
36.
Zurück zum Zitat Brandes JC, Carraway H, Herman JG (2007) Optimal primer design using the novel primer design program: MSPprimer provides accurate methylation analysis of the ATM promoter. Oncogene 26:6229–6237CrossRefPubMed Brandes JC, Carraway H, Herman JG (2007) Optimal primer design using the novel primer design program: MSPprimer provides accurate methylation analysis of the ATM promoter. Oncogene 26:6229–6237CrossRefPubMed
37.
Zurück zum Zitat Graff JR, Herman JG, Myohanen S et al (1997) Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation. J Biol Chem 272:22322–22329CrossRefPubMed Graff JR, Herman JG, Myohanen S et al (1997) Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation. J Biol Chem 272:22322–22329CrossRefPubMed
38.
Zurück zum Zitat Ponchon T, Gagnon P, Berger F et al (1995) Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study. Gastrointest Endosc 42:565–572CrossRefPubMed Ponchon T, Gagnon P, Berger F et al (1995) Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study. Gastrointest Endosc 42:565–572CrossRefPubMed
39.
Zurück zum Zitat Tada M, Yokosuka O, Omata M et al (1990) Analysis of ras gene mutations in biliary and pancreatic tumors by polymerase chain reaction and direct sequencing. Cancer 66:930–935CrossRefPubMed Tada M, Yokosuka O, Omata M et al (1990) Analysis of ras gene mutations in biliary and pancreatic tumors by polymerase chain reaction and direct sequencing. Cancer 66:930–935CrossRefPubMed
Metadaten
Titel
CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma
verfasst von
Baek-hui Kim
Nam-Yun Cho
So Hyun Shin
Hyeong-Ju Kwon
Ja June Jang
Gyeong Hoon Kang
Publikationsdatum
01.10.2009
Verlag
Springer-Verlag
Erschienen in
Virchows Archiv / Ausgabe 4/2009
Print ISSN: 0945-6317
Elektronische ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-009-0829-4

Weitere Artikel der Ausgabe 4/2009

Virchows Archiv 4/2009 Zur Ausgabe

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Open Access Biomarker Leitthema

Um auch an kleinen Gewebeproben zuverlässige und reproduzierbare Ergebnisse zu gewährleisten ist eine strenge Qualitätskontrolle in jedem Schritt des Arbeitsablaufs erforderlich. Eine nicht ordnungsgemäße Prüfung oder Behandlung des …

Vergleichende Pathologie in der onkologischen Forschung

Pathologie Leitthema

Die vergleichende experimentelle Pathologie („comparative experimental pathology“) ist ein Fachbereich an der Schnittstelle von Human- und Veterinärmedizin. Sie widmet sich der vergleichenden Erforschung von Gemeinsamkeiten und Unterschieden von …

Gastrointestinale Stromatumoren

Open Access GIST CME-Artikel

Gastrointestinale Stromatumoren (GIST) stellen seit über 20 Jahren ein Paradigma für die zielgerichtete Therapie mit Tyrosinkinaseinhibitoren dar. Eine elementare Voraussetzung für eine mögliche neoadjuvante oder adjuvante Behandlung bei …

Personalisierte Medizin in der Onkologie

Aufgrund des erheblichen technologischen Fortschritts in der molekularen und genetischen Diagnostik sowie zunehmender Erkenntnisse über die molekulare Pathogenese von Krankheiten hat in den letzten zwei Jahrzehnten ein grundlegender …