Universität zu Köln

Garcia, Tancia (2024). Tracing tumor evolution in ganglioneuroblastoma, nodular subtype. PhD thesis, Universität zu Köln.

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Abstract

Ganglioneuroblastoma, nodular subtype, (GNBn) is a rare, pediatric, peripheral Neuroblastic Tumor (pNT) of the sympathetic nervous system with mostly poor clinical outcome. Two thirds of Ganglioneuroblastoma, nodular subtype, are classified into the unfavorable subset. This childhood malignancy is characterized as a composite tumor with two different histological components: the ganglioneuromatous and the neuroblastic component. It has remained uncertain, however, whether tumor cells of these two components are clonally related. In addition, it is still unclear which factors enable terminal differentiation in parts of the tumor, whereas other parts stay in a poorly differentiated state. GNBn is significantly heterogenous in outcome and its biology remains elusive, making further characterization of this entity necessary. In this study, we have established a protocol to characterize neuroblasts and ganglionic cells individually using Laser Capture Microdissection. DNA of microdissected neuroblasts and ganglionic cells of 5 GNBn tumor samples in stage 4 was extracted and whole-genome sequenced. Mutations were called and subsequently validated through dideoxy-sequencing. Neuroblasts and ganglionic cells shared several mutations, while only selected mutations occurred in either cell type. In one case, biallelic inactivation of MAP2K7 was found in neuroblasts, while ganglionic cells harbored a heterozygous mutation of MAP2K7 only. Five additional neuroblastic tumors with a biallelic inactivation of MAP2K7 were identified in our neuroblastoma sequencing data base. All six tumors lacked other frequent alterations of neuroblastoma, i.e., MYCN amplification, ATRX mutation, or TERT rearrangement. The study demonstrated that ganglionic and neuroblastic cells are clonally related, as they shared several mutations. We also found evidence, however, that neuroblasts harbor private genomic alterations, such as inactivating mutations of MAP2K7 and ATRX, which may account for the malignant properties of this cell type and their inability to differentiate in stage 4 GNBn. By contrast, malignant neuroblasts may differentiate into senescent ganglionic cells in the absence of such mutations.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Garcia, Tancia UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-730256
Date:	February 2024
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Kinder- und Jugendmedizin > Klinik und Poliklinik für Kinder- und Jugendmedizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Alternative Lengthening of Telomeres, Ganglioneuroblastoma, nodular subtype, Ganglionic cells, neuroblasts, Telomere Maintenance Mechanism, peripheral Neuroblastic Tumor, MYCN amplification, ATRX mutation, TERT rearrangement, Neuroblastoma, Ganglioneuroblastoma, intermixed, Ganglioneuroma, Laser Capture Microdissection, whole-genome sequencing, genomic libraries, MAP2K7, Mitogen Activated Protein Kinase Kinase 7, MKK7, JNK signaling pathway, malignant transformation, tumor evolution English
Date of oral exam:	February 2024
Referee:	Name Academic Title Fischer, Matthias Universitätsprofessor Dr. med. Montesinos-Rongen, Manuel Professor Dr. rer. nat.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/73025