Mutacijski potpisi ultraljubičastog zračenja u melanomu uvee i melanomu kože čovjeka

master's thesis

• Title (english): Ultraviolet radiation mutational signatures in human uveal and skin melanoma
• Author: Barbara Maračić
• Mentor: Rosa Karlić (mentor)
• Mentor: Paula Štancl (komentor)
• Committee member: Rosa Karlić (predsjednik povjerenstva)
• Committee member: Petra Korać (član povjerenstva)
• Committee member: Inga Urlić (član povjerenstva)
• Committee member: Maja Matulić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2023-11-30, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Melanomi uvee i kože su dva različita tumorska tipa koja nastaju iz melanocita, stanica odgovornih za sintezu pigmenta melanina. Iako dijele zajedničku ishodišnu stanicu tumora, različiti egzogeni i endogeni čimbenici uzrokuju specifične obrasce mutacija koje nazivamo mutacijskim potpisima. Cilj ovog istraživanja je okarakterizirati i usporediti mutacije i mutacijske potpise prisutne u melanomima uvee i kože s naglaskom na mutacije u genima biomarkerima. Analizirane mutacije dobivene su sekvenciranjem cijelih eksoma 80 pacijenata melenoma uvee i 468 pacijenata melanoma kože, javno dostupnih u TCGA bazi podataka. Mutacijski potpisi pozvani su “refitting”-metodom potpisa COSMIC. Fisherov test primijenjen je za analizu diferencijalno mutiranih gena i biomarkera između melanoma, a Mann-Whitney U test i jednostrani jednoproporcijski Z-test za testiranje povezanosti specifičnih mutacijskih potpisa s mutacijama u genima biomarkerima. Rezultati ukazuju na diferencijalne mutacijske profile oba melanoma, kao i na diferencijalne mutacijske procese uključene u mutagenezu melanoma. Dok u melanomu kože prevladavaju UV mutacijski potpisi (SBS7b i SBS7a) oni su slabo zastupljeni u melanomu uvee. UV zračenje pokazalo se odgovornim za nastanak pokretačkih mutacija u biomarkerima BRAF, NRAS i CDKN2A melanoma kože, dok su za mutagenezu biomarkera melanoma uvee odgovorni drugi mutacijski procesi poput potpisa aristolohične kiseline SBS22 odgovornog za mutagenezu GNA11.

Abstract (english)

Uveal and skin melanoma are two distinct tumor types arising from melanocytes, cells producing melanin pigment. Despite their common cell of origin, different exogenous and endogenous factors lead to specific mutational patterns known as mutational signatures. This research aims to characterize and compare the mutations and mutational signatures in uveal and skin melanoma, focusing on the mutations in the biomarker genes. The analysis examined the whole exome sequencing data of 80 uveal melanoma patients and 468 skin melanoma patients, publicly available in the TCGA database. Mutational signatures were called using the COSMIC signature refitting method. Fisher’s test was applied to analyze the differentially mutated genes and biomarkers between the melanomas, and the Mann-Whitney U test and one-tailed One-Proportion Z-Test to test the correlation between the specific mutational signatures and biomarker mutations. The results indicate differential mutational profiles of the melanomas, as well as differential mutational processes involved in melanoma mutagenesis. While UV mutational signatures (SBS7b and SBS7a) are predominant in skin melanoma, they are poorly represented in uveal melanoma. UV radiation seems to be responsible for driver mutations in the BRAF, NRAS, and CDKN2A biomarkers in skin melanoma, while other mutational processes are responsible for mutagenesis of uveal melanoma biomarkers, such as aristolochic acid signature SBS22 for GNA11 mutagenesis.

• Keywords: tumor; eksom; biomarker; pokretačka mutacija; mutacijski potpis
• Keywords (english): tumor; exome; biomarker; driver mutation; mutational signature
• Language: croatian
• URN:NBN: urn:nbn:hr:217:426033
• Study programme: Title: Molecular Biology-University graduate programme; Study programme type: university; Study level: graduate; Academic / professional title: sveučilišni/a magistar/magistra molekularne biologije (sveučilišni/a magistar/magistra molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2025-11-30
• Created on: 2024-01-11 11:27:17