Association between genetic variants and risk of melanoma (Doctoral thesis)
The development of melanoma is a complex process involving the interplay of environmental, phenotypic and genetic risk factors. Novel findings of predisposing genetic variants for melanoma risk may result to deeper understanding of its pathophysiology and to evaluating melanoma cases based on their genetic profile, toward more precise disease risk prediction. In the current thesis, we first attempt to validate an extensive set of SNPs previously associated with melanoma risk in an independent sample of melanoma patients and healthy controls from Greece. In addition, we assessed the cumulative impact of the genetic variants on melanoma risk prediction by calculating a weighted genetic risk score (GRS). Fifteen independent SNPs were significantly associated with melanoma (P<0.05). GRS was strongly associated with melanoma risk, but achieves a modest improvement in risk prediction when added to a phenotypic risk model. We next tried to establish novel susceptibility genetic variants for melanoma by assessing candidate genes in the largest GWAS for melanoma up to date. For our selected genetic variant, no genome-wide significant estimates were obtained (P=1.95x10-5) despite the large number of melanoma cases used in the analysis (Ν=16,534). Next, we examined the role of sun exposure in individuals with higher risk of melanoma incidence based on genetic predisposition within UK Biobank. A weighted GRS was calculated based on previously reported genetic variants that achieved genome-wide significance in their association with melanoma and we divided the population sample in groups of high and low genetic risk. GRS and sun exposure were strongly associated with the risk of melanoma. Among participants at high genetic risk, every additional hour of sun exposure increases the risk of melanoma incidence by 4%. Those results reinforce precision medical practices with the aim of preventing melanoma, especially in individuals at higher genetic risk. Finally, in the current thesis, we performed Mendelian Randomization to test the possible causal relationship between genetically predicted dietary factors and melanoma. We used summary statistics from the largest GWASs up to date for coffee consumption, beta-carotene intake, retinol intake, and serum vitamin D and from UK Biobank for melanoma. The results showed that there is no significant causal relationship between the selected dietary factors and risk of melanoma. As a next step in this analysis, new data on melanoma cases will be added by the MelaNostrum consortium, which investigates the risk of melanoma in the Mediterranean countries.
|Institution and School/Department of submitter:||Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής|
|Keywords:||Μελανωμα,Γενετικοί πολυμορφισμοί,Μοντέλα πρόβλεψης,Αλληλεπιδράσεις γονιδίων-περιβάλλοντος,Melanoma,Genetic variants,Prediction models,Gene-environment interactions|
|Appears in Collections:||Διδακτορικές Διατριβές|
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|Δ.Δ. ΝΤΡΙΤΣΟΣ ΓΕΩΡΓΙΟΣ 2018.pdf||2.63 MB||Adobe PDF||View/Open|
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