nach oben

Erschienen in:

01.01.2009 | Original Article

Progression of Hypermethylation of the p16 ^INK4A Gene from Normal Liver to Nontumorous Liver and Hepatocellular Carcinoma: An Evaluation Using Quantitative PCR Analysis

verfasst von: So Kurita, Shogo Ohkoshi, Masahiko Yano, Kazuhide Yamazaki, Kenta Suzuki, Yo-hei Aoki, Yasunobu Matsuda, Toshifumi Wakai, Yoshio Shirai, Takafumi Ichida, Yutaka Aoyagi

Erschienen in: Digestive Diseases and Sciences | Ausgabe 1/2009

Einloggen, um Zugang zu erhalten

Abstract

The aim of this study was to determine to what extent hypermethylation of the p16 ^INK4A (p16) gene promoter is increased in nontumorous liver tissues compared with in normal liver, using two quantitative methylation-specific polymerase chain reaction (MS-PCR) methods and a bisulfite sequencing method. Methylation of the p16 gene was detected more frequently in nontumorous liver than in normal liver using the TaqMan PCR method. Methylation indices also were significantly higher in nontumorous than in normal liver. However, the bisulfite sequencing method did not detect significantly more methylation of the p16 gene in nontumorous than normal liver, nor was there a significant difference in the level of p16 mRNA. There may be a greater proportion of cells which contain methylated p16 in nontumorous than in normal liver. However, the difference was so small that the functional relevance to hepatocarcinogenesis remains elusive.

Okuda K. Hepatocellular carcinoma: recent progress. Hepatology. 1992;15:948–963.PubMedCrossRef

Shiratori Y, Yoshida H, Omata M. Different clinicopathological features of hepatocellular carcinoma in relation to causative agents. J Gastroenterol. 2001;36:73–78.PubMedCrossRef

Feitelson MA, Sun B, Satiroglu Tufan NL, Liu J, Pan J, Lian Z. Genetic mechanisms of hepatocarcinogenesis. Oncogene. 2002;21:2593–2604.PubMedCrossRef

Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674–687.PubMedCrossRef

Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141–196.PubMedCrossRef

Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3:415–428.PubMedCrossRef

Bird A. The essentials of DNA methylation. Cell. 1992;70:5–8.PubMedCrossRef

Belinsky SA, Nikula KJ, Palmisano WA, et al. Aberrant methylation of p16 ^INK4a is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci USA. 1998;95:11891–11896.PubMedCrossRef

Hsieh CJ, Klump B, Holzmann K, Brochard F, Gregor M, Porschen R. Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res. 1998;58:3942–3945.PubMed

10.

Klump B, Hsieh CJ, Holzmann K, Gregor M, Porschen R. Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett’s esophagus. Gastroenterology. 1998;115:1381–1386.PubMedCrossRef

11.

Wilentz RE, Geradts J, Maynard R, et al. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res. 1998;58:4740–4744.PubMed

12.

Lee JH, Park SJ, Abraham SC, et al. Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas. Oncogene. 2004;23:4646–4654.PubMedCrossRef

13.

Kaneto H, Sasaki S, Yamamoto H, et al. Detection of hypermethylation of the p16 ^INK4A gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus. Gut. 2001;48:372–377.PubMedCrossRef

14.

Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol. 2003;163:1371–1378.PubMed

15.

Di Gioia S, Bianchi P, Destro A, et al. Quantitative evaluation of RASSF1A methylation in the non-lesional, regenerative and neoplastic liver. BMC Cancer. 2006;6:89–100.PubMedCrossRef

16.

Lo YM, Wong IH, Zhang J, Tein MS, Ng MH, Hjelm NM. Quantitative analysis of aberrant p16 methylation using real-time quantitative methylation-specific polymerase chain reaction. Cancer Res. 1999;59:3899–3903.PubMed

17.

Hoque MO, Begum S, Topaloglu O, et al. Quantitative detection of promoter hypermethylation of multiple genes in the tumor, urine, and serum DNA of patients with renal cancer. Cancer Res. 2004;64:5511–5517.PubMedCrossRef

18.

Lehmann U, Berg-Ribbe I, Wingen LU, et al. Distinct methylation patterns of benign and malignant liver tumors revealed by quantitative methylation profiling. Clin Cancer Res. 2005;11:3654–3660.PubMedCrossRef

19.

Harden SV, Tokumaru Y, Westra WH, et al. Gene promoter hypermethylation in tumors and lymph nodes of stage I lung cancer patients. Clin Cancer Res. 2003;9:1370–1375.PubMed

20.

Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994;368:753–756.PubMedCrossRef

21.

Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366:704–707.PubMedCrossRef

22.

Baek MJ, Piao Z, Kim NG, et al. p16 is a major inactivation target in hepatocellular carcinoma. Cancer. 2000;89:60–68.CrossRef

23.

Matsuda Y, Ichida T, Matsuzawa J, Sugimura K, Asakura H. p16 ^INK4A is inactivated by extensive CpG methylation in human hepatocellular carcinoma. Gastroenterology. 1999;116:394–400.PubMedCrossRef

24.

Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S. Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis—a comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma. Hepatology. 2000;32:970–979.PubMedCrossRef

25.

Roncalli M, Bianchi P, Bruni B, et al. Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma. Hepatology. 2002;36:427–432.PubMedCrossRef

26.

Li X, Hui AM, Sun L, et al. p16^INK4A hypermethylation is associated with hepatitis virus infection, age, and gender in hepatocellular carcinoma. Clin Cancer Res. 2004;10:7484–7489.PubMedCrossRef

27.

Qin Y, Liu JY, Li B, Sun ZL, Sun ZF. Association of low p16INK4a and p15INK4b mRNAs expression with their CpG islands methylation with human hepatocellular carcinogenesis. World J Gastroenterol. 2004;10:1276–1280.PubMed

28.

Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Sheuer PJ. Classification of chronic hepatitis: diagnosis, grading, and staging. Hepatology. 1994;19:1513–1520.PubMedCrossRef

29.

Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA. 1996;93:9821–9826.PubMedCrossRef

30.

Kim BN, Yamamoto H, Ikeda K, et al. Methylation and expression of p16^INK4A tumor suppressor gene in primary colorectal cancer tissues. Int J Oncol. 2005;26:1217–1226.PubMed

31.

Clark SJ, Harrison J, Paul CL, Frommer M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res. 1994;22:2990–2997.PubMedCrossRef

32.

Issa JP. CpG-island methylation in aging and cancer. Curr Top Microbiol Immunol. 2000;249:101–118.PubMed

33.

Waki T, Tamura G, Sato M, Motoyama T. Age-related methylation of tumor suppressor and tumor-related genes: an analysis of autopsy samples. Oncogene. 2003;22:4128–4133.PubMedCrossRef

34.

Narimatsu T, Tamori A, Koh N, et al. p16 promoter hypermethylation in human hepatocellular carcinoma with or without hepatitis virus infection. Intervirology. 2004;47:26–31.PubMedCrossRef

35.

Muhlisch J, Bajanowski T, Rickert CH, et al. Frequent but borderline methylation of p16 ^INK4A and TIMP3 in medulloblastoma and sPNET revealed by quantitative analyses. J Neurooncol. 2007;83:17–29. (online first).PubMedCrossRef

Titel: Progression of Hypermethylation of the p16 INK4A Gene from Normal Liver to Nontumorous Liver and Hepatocellular Carcinoma: An Evaluation Using Quantitative PCR Analysis
verfasst von: So Kurita
Shogo Ohkoshi
Masahiko Yano
Kazuhide Yamazaki
Kenta Suzuki
Yo-hei Aoki
Yasunobu Matsuda
Toshifumi Wakai
Yoshio Shirai
Takafumi Ichida
Yutaka Aoyagi
Publikationsdatum: 01.01.2009
Verlag: Springer US
Erschienen in: Digestive Diseases and Sciences / Ausgabe 1/2009
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-008-0611-5

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Reizdarmsyndrom: Diäten wirksamer als Medikamente

29.04.2024 Reizdarmsyndrom Nachrichten

Bei Reizdarmsyndrom scheinen Diäten, wie etwa die FODMAP-arme oder die kohlenhydratreduzierte Ernährung, effektiver als eine medikamentöse Therapie zu sein. Das hat eine Studie aus Schweden ergeben, die die drei Therapieoptionen im direkten Vergleich analysierte.

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2009

Choledochal Cyst Complications Presenting as Duodenal Obstruction in an 82-Year-Old Patient with Gallbladder Agenesis

Presence of Lymph Node Vasculature: A New EUS Criterion for Benign Nodes?

Infective Endoshuntitis in a Patient with Non-cirrhotic Portal Hypertension: Successful Medical Management

Adrenomedullin as Preventive Treatment in Cerulein-induced Acute Pancreatitis

Endoscopic and Histopathologic Findings Associated with H. pylori Infection in Very Young Children