Lasorsa, Vito Alessandro (2021) Neuroblastoma somatic mutations enriched in cis-regulatory elements collectively affect genes involved in embryonic development and immune system response. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: Neuroblastoma somatic mutations enriched in cis-regulatory elements collectively affect genes involved in embryonic development and immune system response
Lasorsa, Vito
Date: 2021
Number of Pages: 54
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 33
Coordinatore del Corso di dottorato:
Date: 2021
Number of Pages: 54
Keywords: Cis-regulatory elements, Somatic mutations, Neuroblastoma
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/03 - Genetica medica
Date Deposited: 21 Feb 2021 11:06
Last Modified: 07 Jun 2023 10:21

Collection description

Background | The ever-growing interest towards noncoding cis-regulatory variants as cancer drivers is currently hampered by numerous challenges and limitations of variant prioritization and interpretation methods and tools. Methods | To overcome these limitations, I focused on active cis regulatory elements (aCREs) to design a customized panel for deep sequencing of 56 neuroblastoma tumor and normal DNA sample pairs. CREs were defined by a reanalysis of H3K27ac ChiP-seq peaks of 25 neuroblastoma cell lines. aCREs were further identified by the presence of open chromatin as defined by DNase Hypersensitivity sites. This provided a small subset of genomic regions with evident regulatory functions in which to search for driver mutations. I tested these regions for an excess of somatic mutations and assessed the statistical significance with a global approach accounting for chromatin accessibility and replication timing. Additional validation was provided by analyzing whole genome sequences of 151 neuroblastomas. For the mutated regions, I determined their candidate target genes through HiC data analysis. Results | I identified a significant excess of somatic mutations in aCREs of diverse genes including IPO7, HAND2, and ARID3A. A gene expression signature built on basis of these three, and nearby, interacting genes strongly correlated with negative prognostic markers and low survival rates of patients affected by neuroblastoma. Moreover, I observed a convergence of biological functions of the target genes of mutated aCREs and transcription factors with binding motifs altered by mutations towards processes related to embryonic development and immune system response. Conclusion | My strategy led me to identify somatic mutations in regulatory elements that collectively can drive neuroblastoma onset.


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