Dokument: Decoding Germline and Somatic Genomes of Children with Cancer through Optical Genome Mapping and Next-Generation Sequencing
| Titel: | Decoding Germline and Somatic Genomes of Children with Cancer through Optical Genome Mapping and Next-Generation Sequencing |
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=73800 |
| URN (NBN): | urn:nbn:de:hbz:061-20260713-135039-7 |
| Kollektion: | Dissertationen |
| Sprache: | Englisch |
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation |
| Medientyp: | Text |
| Autor: | Brandes, Danielle [Autor] |
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| Beitragende: | Prof. Dr. Borkhardt, Arndt [Gutachter] Prof. Dr. Wesselborg, Sebastian [Gutachter] |
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit |
| Beschreibung: | Genomic variation plays a significant role in pediatric cancers, contributing to both oncogenic somatic driver events and inherited cancer predisposition. While pathogenic single nucleotide variants have been extensively described and are well characterized, the contribution of larger structural variants (SVs) in this context are less understood. The full impact of these alterations still needs to be elucidated. Traditional cytogenetic methods and short-read based next-generation sequencing (NGS) approaches have limitations in comprehensively detecting the full spectrum of such larger genomic lesions. Optical genome mapping (OGM) and long-read sequencing are emerging new technologies that are capable of reliably detecting SVs in constitutional and cancer genomes. This thesis is based on two original publications that explore the application of advanced genomic technologies and NGS-based integration in distinct contexts of pediatric cancer diagnosis and research.
The first original publication focuses on patients with a potential underlying cancer predisposition syndrome but non-conclusive results from whole-exome sequencing (WES). OGM was applied to perform an unbiased screening of germline structural variation in 34 pediatric cancer patients, including available parental samples. The study identified a median of 49 rare SVs per patient and three de novo alterations based on 18 child-parent trios. Notably, two significant germline alterations were highlighted that were discovered in two respective leukemia patients: (i) a likely pathogenic deletion of exon three in the known cancer predisposition gene BRCA2, segregating within a family with a history of breast cancer; and (ii) a de novo duplication affecting a potentially new cancer predisposition gene candidate RPA1. Functional testing of patient-derived cells compared to non-affected cells showed that RPA1 duplication might increase the sensitivity to genotoxic agents. The second original publication applied OGM with multi-omics integration in a cohort of 60 pediatric BCP-ALL cases focusing on the two most common genetic subtypes, ETV6::RUNX1 (E::R) translocated and classical hyperdiploid (HD) BCP-ALL. OGM was combined with conventional cyto- and molecular genetic methods, WES data, and targeted validation through long-read and RNA sequencing to comprehensively characterize the genetic somatic landscape and novel recurrent genetic events. OGM demonstrated a 95% concordance with SVs in diagnostic samples previously reported by molecular cytogenetics and SNP-arrays. As frontline method, OGM detected 677 additional SVs that were missed by regular diagnostic testing, including prognostically relevant focal deletions affecting genes such as IKZF1. The study further demonstrated that SV profiles of E::R and HD BCP-ALL are profoundly different, with E::R cases harboring 2.7-fold more SVs, particularly focal deletions, compared to HD BCP-ALL. Integration of OGM and WES data identified 52 minimal altered regions (MARs) in the analyzed pediatric BCP-ALL cohort, including 19 recurrent regions that reveal potential novel leukemic drivers such as FOCAD, IKBKB, MIB1 as well as double-hit targets STAG2 and MANBA. Additionally, nine translocations were detected that may lead to novel in-frame fusion genes. In conclusion, this thesis contributes to the development of a genomic reference platform for the identification and interpretation of structural variation in both germline and somatic genomes of children with cancer. Both presented studies demonstrate the advantage of integrating genomic technologies such as OGM with NGS-based methods. Together, these findings reveal a more comprehensive spectrum of genomic alterations, offering novel insights into pediatric cancer predisposition and mechanisms underlying leukemogenesis of pediatric BCP-ALL. This work provides a foundation for future functional studies and clinical investigations aimed at improving diagnosis, risk stratification and treatment in pediatric oncology. |
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz |
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät |
| Dokument erstellt am: | 13.07.2026 |
| Dateien geändert am: | 13.07.2026 |
| Promotionsantrag am: | 25.09.2025 |
| Datum der Promotion: | 23.01.2026 |
