Dokument: Molecular characterization of early precursors of pancreatic ductal adenocarcinoma
| Titel: | Molecular characterization of early precursors of pancreatic ductal adenocarcinoma | |||||||
| Weiterer Titel: | Molekulare Charakterisierung von frühen Vorstufen des duktalen Adenokarzinoms der Bauchspeicheldrüse | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=60208 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20230809-090249-7 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Frohn, Lisa [Autor] | |||||||
| Dateien: |
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| Beitragende: | Univ.-Prof. Dr. med. Irene Esposito [Gutachter] Prof. Dr. Martin, William [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality rates due to late diagnosis and rapid progression. Therefore, better tools for earlier detection are urgently needed. The most common PDAC precursor lesions are pancreatic intraepithelial neoplasias (PanIN) and intraductal papillary mucinous neoplasms (IPMN). The gastric subtype of IPMN shares morphological homologies with PanIN and the two lesions are currently distinguished only according to their size. However, their outcome differs highly so that stringent criteria for proper differentiation are mandatory. This study aims at characterizing the molecular features of these two PDAC precursors for a better understanding of their biological behavior.
120 cases of resected IPMN and/or PanIN were retrospectively evaluated and reclassified according to morphologic and immunohistochemical criteria. In total, 59 different precursors were analyzed via NGS with a customer-designed gene panel with 22 cancer-related genes. For copy number variation detection, low-coverage whole-genome sequencing was done with formalin fixed paraffin embedded (FFPE) material from 47 cases. For transcription data, RNASeq was performed with 7 different samples (3 gastric IPMN and 4 PanIN) and 7 controls (3 acinar tissue and 4 PDAC samples). For methylation status, the Illumina Infinium MethylationEPIC Array was performed in 49 samples (including 18 gastric IPMN, 8 PanIN samples, 10 intestinal IPMN samples and 13 different control samples Targeted NGS confirmed the presence of the two driver mutations in the KRAS and GNAS genes in gastric and intestinal IPMN. In the copy number profile, the PanIN lesions did not display recurrent copy numbers in opposition to gastric IPMN, which had CNV in defined regions. Intestinal IPMN showed the most aberrant copy number profile, suggesting a higher transformational potential. The methylation profile indicated a high similarity between PanIN and gastric IPMN, where only 0.36 % of the 5'-Cytosine-phosphate-Guanine-3' sites (CpGs) were differently methylated in contrast to the completely different methylation profile of the intestinal IPMN. Based on the methylation analysis, the cell of origin of gastric IPMN and PanIN seems to be derived from the acinar compartment, whereas the cell of origin of intestinal IPMN is derived from the ductal compartment. The transcriptome analysis was performed to compare gastric IPMN and PanIN and showed that 595 significantly different expressed genes (DEGs) were present in the two lesions (p-value < 0.01). By combining the significantly different expressed and methylated genes in an integrative analysis between PanIN and gastric IPMN, 3 different hub genes were chosen for further investigation, including the genes MUC6, TFF1 and KLF4. The prospect marker genes were tested by immunochemistry in a cohort of 71 patients on TMA slides. The expression pattern on the protein level did not reflect the mRNA level and these markers were not suitable for detection or to distinguish the different precursors from each other. The higher expression of these genes, the copy number profile and the different activation of the downstream pathways support the concept of higher neoplastic potential of gastric IPMN compared to PanIN. In conclusion, gastric IPMN and PanIN have a very similar morphology, genetics and methylation profile but differ in the CNV and transcriptome profile. Our data indicate a common origin with the acquisition of a higher neoplastic potential by gastric IPMN. Intestinal IPMN are distinct entities with a clear-cut neoplastic potential already in low grade lesions with completely different methylation and copy number profile. Our data show that the genomic based data can separate the different subtypes of PDAC precursors in harmony with the immunophenotypical profile. As long as no validated markers are found, the immunophenotypical subtyping is fundamental in identifying precursors with different risks of progression and should be included as core element in pathology reports. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 09.08.2023 | |||||||
| Dateien geändert am: | 09.08.2023 | |||||||
| Promotionsantrag am: | 26.10.2021 | |||||||
| Datum der Promotion: | 25.03.2022 |
