Dokument: Aberrante Methylierung des APC-Promotors als Tumormarker für die molekularzytologische Diagnostik des Lungenkarzinoms an Bronchialaspiraten
| Titel: | Aberrante Methylierung des APC-Promotors als Tumormarker für die molekularzytologische Diagnostik des Lungenkarzinoms an Bronchialaspiraten | |||||||
| Weiterer Titel: | Aberrant methylation of the adenomatous polyposis coli promoter 1A in bronchial aspirates from patients with suspected lung cancer | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=38349 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20160519-102839-6 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Mostakiem, Ariana [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Biesterfeld, Stefan [Betreuer/Doktorvater] Prof. Dr. Schulz, Wolfgang A. [Gutachter] | |||||||
| Stichwörter: | APC, Methylierung, Tumormarker | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Die Promotor-Hypermethylierung ist ein wichtiger Mechanismus in der funktionellen Gen-Ausschaltung und bietet daher einen vielversprechenden Ausgangspunkt zur Entwicklung von molekularen Biomarkern. Ziel dieser Arbeit war, aberrante Promotormethylierung des APC-Gens (adenomatous polyposis coli) in Bezug auf Prävalenz und quantitativen Methylierungsgrad in Bronchialaspiraten von Patienten mit Tumorverdacht zu bestimmen. Der Nachweis der APC-Promotormethylierung erfolgte an DNA aus Bronchialaspiraten nach Bisulfitkonversion mittels quantitativer methylierungsspezifischer real-time PCR (QMSP). Es wurden in einer retrospektiven Fall-Kontrollstudie unter Verwendung der QMSP sowohl 155 Bronchialaspirate von Patienten mit nicht-kleinzelligem (NSCLC) bzw. kleinzelligem Karzinom der Lunge als auch 67 Bronchialaspirate von Nichttumorpatienten untersucht. Die quantitative methylierungsspezifische PCR (QMSP) erlaubt den sensitiven und spezifischen Nachweis von Promotormethylierung und bietet die Möglichkeit, durch Hinzunahme eines Referenzgens, hier MYOD1 (myogenic differentiation 1), den Methylierungsnachweis zu quantifizieren und somit einen Schwellenwert (Cut off) einzuführen, der eine bessere Diskriminierung zwischen benigner und maligner Lungenerkrankung gestattet. Eine aberrante Promotormethylierung von APC - vor Beginn der Fall-Kontroll-Studie zunächst definiert als Überschreiten eines Schwellenwertes (APC/ MYOD1 x100) von 5,- wurde insgesamt bei 71% der Bronchialaspirate von NSCLC Pateinten, 38% von SCLC Patienten und 42% der Nicht-Tumorpatienten gefunden. Die Spezifität war mit 58% nicht geeignet, APC-Methylierung als Biomarker in der Lungenkarzinomdiagnostik zu verwenden. Nach Einführung eines Schwellenwertes bei einem Methylierungslevel ≥ 35 verblieb nur noch das Bronchialaspirat eines Nichttumorpatienten, welches eine hohe Methylierung des APC-Promotors aufwies (Spezifität 98,5%). 45 der 155 Bronchialaspirate von Tumorpatienten zeigten eine hohe Methylierung des APC-Promotors (Sensitivität 29%), Die Prävalenz aberranter APC-Promotor-Methylierungen in Bronchialaspiraten der Kontrollgruppe macht deutlich, dass APC für einen Tumornachweis eine sehr hohe Spezifität zeigt und daher, aufgrund der nicht ganz optimalen Sensitivität vorzugsweise in Kombination mit anderen Biomarkern als Tumormarker zur molekularbiologischen Diagnostik von Lungentumoren gut geeignet ist.Promoter hypermethylation is a major mechanism for gene silencing and offers a promising starting point for developing molecular biomarkers. The purpose of our study was to determine aberrant methylation of the adenomatous polyposis coli (APC) gene promoter 1A with respect to its prevalence and quantitative level in bronchial aspirates from patients with suspected lung cancer. Applying quantitative methylation-specific PCR, 155 bronchial aspirates from patients with non-small cell cancer (NSCLC) and small cell cancer (SCLC) of the lung as well as 67 bronchial aspirates from patients diagnosed for nonneoplastic lung disease were examined in a retrospective case-control study. . In contrast, quantitative analysis showed a Aberrant APC promoter 1A methylation was seen in 71% of NSCLCs, 38% of SCLCs and 42% of patients with nonneoplastic lung disease, being therefore not specific for the presence of primary lung cancersignificantly higher methylation level of bronchial aspirates from NSCLC as compared to patients without neoplastic lung disease. Introducing a cutoff point that defined high level of APC hypermethylation NSCLC could be discriminated from cases without neoplastic disease with a specificity of 98.5% and a sensitivity of 34%. The data suggest that quantitative analysis of APC hypermethylation may serve as a biomarker of primary lung cancer | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 19.05.2016 | |||||||
| Dateien geändert am: | 19.05.2016 | |||||||
| Promotionsantrag am: | 30.03.2011 | |||||||
| Datum der Promotion: | 12.04.2016 |
