Aievola, Vincenzo (2024) Noncoding regulatory mutations as driving event for the oncogenic core regulatory circuitries of neuroblastoma. [Tesi di dottorato]
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| Tipologia del documento: | Tesi di dottorato |
|---|---|
| Lingua: | English |
| Titolo: | Noncoding regulatory mutations as driving event for the oncogenic core regulatory circuitries of neuroblastoma |
| Autori: | Autore Email Aievola, Vincenzo vincenzo.aievola@unina.it |
| Data: | 7 Marzo 2024 |
| Numero di pagine: | 105 |
| Istituzione: | Università degli Studi di Napoli Federico II |
| Dipartimento: | Ingegneria Elettrica e delle Tecnologie dell'Informazione |
| Dottorato: | Computational and quantitative biology |
| Ciclo di dottorato: | 36 |
| Coordinatore del Corso di dottorato: | nome email Ceccarelli, Michele michele.ceccarelli@unina.it |
| Tutor: | nome email Capasso, Mario [non definito] |
| Data: | 7 Marzo 2024 |
| Numero di pagine: | 105 |
| Parole chiave: | Neuroblastoma; Genomics; somatic mutations; NGS |
| Settori scientifico-disciplinari del MIUR: | Area 06 - Scienze mediche > MED/03 - Genetica medica |
| Depositato il: | 19 Giu 2024 12:20 |
| Ultima modifica: | 30 Mar 2026 08:36 |
| URI: | http://www.fedoa.unina.it/id/eprint/15536 |
Abstract
Background | Neuroblastoma (NB) is a pediatric tumor composed of mesenchymal (MES) and adrenergic-like (ADRN) cells. These identities derive from the dysregulation of normal cell differentiation, imposed by Core Regulatory Circuitries (CRCs). I hypothesize that noncoding somatic single nucleotide variants (SNVs) in CRCs transcription factor binding sites (TFBSs) may underlie such perturbation, promoting tumorigenesis. Methods | MES and ADRN transcriptionally active TFBSs (aTFBSs) were identified integrating 42 ChIP-seq and 12 ATAC-seq experiments in 7 ADRN and 2 MES NB cell lines. Using Fisher test, I tested these regions for an enrichment of somatic SNVs from WGS data of 397 NB patients. This enrichment was correlated with patients clinical and survival data. SNVs in mutated aTFBSs were selected based on their impact on TFBSs through FABIAN-variant. Next, aTFBSs target-genes were identified analyzing promoter capture HiC in 2 ADRN and 2 MES NB cell lines and their expression values were correlated with known NB prognostic markers. Results | I found a significant mutation enrichment in aTFBSs of 5 ADRN and 1 MES TFs (FDR ≤ 0.1), correlated with patients low survival. Then, I selected 689 SNVs affecting the binding of ADRN/MES CRC TFs (Fabian score ≠ 0). Mutated aTFBSs were found to interact with genes involved in pathways of neuronal differentiation, and MES cells proliferation, thus suggesting potential SNVs impact on NB cell identity definition. aTFBSs carrying SNVs with the highest (cut-off ≥ +0.1) or the lowest (cut-off ≤ -0.1) Fabian score, were found to interact with genes whose expression correlated with worse NB outcome. Conclusions | These results demonstrated that somatic noncoding SNVs may act synergistically to promote NB tumorigenesis, impacting genes involved in differentiation processes.
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