Totaro, Francesca (2013) Searching for common hereditable genetic variants associated with risk of neuroblastoma development and progression. [Tesi di dottorato]


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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: Searching for common hereditable genetic variants associated with risk of neuroblastoma development and progression.
Data: 2 Aprile 2013
Numero di pagine: 92
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Genetica e medicina molecolare
Ciclo di dottorato: 25
Coordinatore del Corso di dottorato:
Data: 2 Aprile 2013
Numero di pagine: 92
Parole chiave: Neuroblastoma, SNP, BARD1
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/03 - Genetica medica
Depositato il: 12 Apr 2013 11:05
Ultima modifica: 22 Lug 2014 09:08
DOI: 10.6092/UNINA/FEDOA/9141


Several neuroblastoma (NBL) susceptibility loci located in diverse genes (LINC00340, BARD1, LMO1, DUSP12, HSD17B12, DDX4, IL31RA, HACE1 and LIN28B) have been identified by genome-wide association studies (GWAS). The replication of association studies are mandatory to validate and comprehensively evaluate the impact of the identified NBL variants on disease risk and phenotype. To this purpose, during my PhD program I have genotyped in an Italian population 14 single nucleotide polymorphisms (SNPs), that have already been associated with NBL in European Americans. All NBL susceptibility genes replicated in the Italian dataset except for two of them, and the most significant SNP was rs6435862 in BARD1. Interestingly, BARD1 showed an additional and independent SNP association (rs7585356). This variant also influenced BARD1 mRNA expression in LCLs and NBL cell lines. Moreover, a cumulative effect of risk variants on NBL risk and development of high-risk phenotype was observed in a dose-dependent manner. These results provide further evidence that the risk loci identified in GWAS contribute to NBL susceptibility in distinct populations and strengthen the role of BARD1 as major genetic contributor to NBL risk. Recent studies have demonstrated a role for interleukin(IL)-6, a pro-inflammatory cytokine, in progression and development of diverse cancers. Moreover, it has been demonstrated that the SNP rs1800795 in IL-6 promoter is associated with inferior clinical outcomes in patients with high-risk NBL. In particular, the major allele is reported as associated with lower survival. Thus, it has been analyzed an Italian population to validate these data. The results showed that the SNP was not implicated in susceptibility to NBL development while the minor allele is significantly associated with a reduction of the overall survival, advanced stage, and high-risk phenotype. Moreover, the analysis of expression indicate the minor allele as correlated with increased level of IL-6 expression. Kaplan-Meier analysis demonstrated that high levels of IL-6 were associated with poor outcome. These findings indicate that the biological effect of this SNP in relation to promotion of cancer progression is consistent with the observed decreased survival time.

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