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The influence of gene polymorphisms on DNA methyltransferase on melanoma flow and outcome

dc.contributor.advisorKozomara, Ružica
dc.contributor.otherVekić, Berislav
dc.contributor.otherĐorđević, Boban
dc.contributor.otherMaksimović-Ivanić, Danijela
dc.creatorMarić-Kujundžić, Helena
dc.date.accessioned2021-04-19T09:37:39Z
dc.date.available2021-04-19T09:37:39Z
dc.date.issued2021-02-24
dc.identifier.urihttp://eteze.kg.ac.rs/application/showtheses?thesesId=8024
dc.identifier.urihttps://fedorakg.kg.ac.rs/fedora/get/o:1337/bdef:Content/download
dc.identifier.urihttps://nardus.mpn.gov.rs/handle/123456789/18249
dc.descriptionSAŽETAK UVOD: Nenormalna metilacija DNA ima kritičnu ulogu kod velikog broja različitih maligniteta uključujući melanom. Metilacija DNA je katalizovana od strane DNA metiltransferaza (DNMT) koji su uključeni u održavanje metilacije (DNMT1) i de novo metilacije (DNMT3A i DNMT3B). CILj:Cilj ove disertacije je bio da se odrede učestalosti polimorfizama u DNMT1 genu (rs2228611, rs2228612, rs2114724) i polimorfizama u DNMT3B genu (rs406193 i rs2424932), kod 123 pacijenata sa melanomom i da se utvrde razlike u učestalosti genotipova ispitivanih polimorfizama i povezanost sa kliničkim parametrima bolesti, stadijumom, nodalnim statusom, Breslow indeksom, brojem mitoza, prisustvom tumor infiltrišućih limfocita (TIL). MATERIJAL I METODE: Polimorfizmi u DNMT1 i DNMT3B genu su ispitivani sa predizajniranim SNP esejima metodom alelske diskriminacije na REAL-TIME aparatu. Korišćeni su komercijalno dostupni eseji: TaqMan SNPs i Universal TaqMan MasterMix Genotyping Assay (Applied Biosystems,SAD), prema protokolu proizvođača. REZULTATI: Nosioci varijacije genotipova DNMT1 rs2228612 su imali lošije izglede za ukupno preživljavanje, kao i preživljavanje bez rekurencije (p=0.000 i p=0.000). DNMT1 rs2228612 je povezan sa ulceracijom (p=0.045), nodalnim statusom (p=0.030), progresijom (p=0. 007) i stadijumom bolesti (p=0.003). Univarijantne analize ukazuju da limfociti koji infiltrišu tumore (TIL) mogu biti markeri dobre prognoze kod pacijenata sa melanomom (HR=0.323, [0.127-0.855] 95% CI, p=0.025), dok genotipska distribucija DNMT3B rs406193 polimorfizama je u značajnoj mjeri povezana sa prisustvom TILs (p=0.012). Multivarijantna analiza je pokazala da je DNMT1 (rs2228612) alel nezavistan prognostički faktor kod pacijenata sa melanomom ( HR=12.126 [2.345-62.715] 95% CI) , dok je DNMT3B (rs2424932) izgubio svoju značajnost kao prognostički faktor ZAKLjUČAK: Rezultati naših istraživanja su pokazali po prvi put da polimorfizam rs2228612 DNMT1 gena može biti udružen sa smanjenim ukupnim preživljavanjem pacijenata sa melanomom. Takođe, polimorfizam rs2424932 DNMT3B gena je pokazao snažan trend udruženosti sa progresijom bolesti i rizikom za kraće ukupno preživljavanje pacijenata sa melanomom. Polimorfizam rs406193 DNMT 3B gena je udružen sa povećanim prisustvom tumor infiltrišućih limfocita (TIL) koje su dobar prognostički marker. Ovi nalazi ukazuju da dalja istraživanja u ovom pravcu mogu potencijalno dovesti do otkrića novih molekularnih markera i/ili novih terapija.sr
dc.descriptionABSTRACT INTRODUCTION: Abnormal DNA methylation has a critical role in a wide variety of malignancies including melanoma. DNA methylation is catalyzed by DNA methyltransferases (DNMT) which are involved in maintenance of methylation (DNMT1) and de novo methylation (DNMT3A and DNMT3B). OBJECTIVE: The aim of this dissertation was to determine the frequency of polymorphisms in the DNMT1 gene (rs2228611, rs2228612, rs2114724) and polymorphisms in the DNMT3B gene (rs406193 and rs2424932), at 123 patients with melanoma, and to determine differences in the frequency of genotypes of the polymorphisms examined, and correlation with clinical disease parameters, stage, nodal status, Breslow index, number of mitoses, presence of tumor infiltrating lymphocytes (TIL). MATERIAL AND METHODS: Polymorphisms in the DNMT1 and DNMT3B gene were examined with pre-designed SNP essays by the allelic discrimination method on the REALTIME apparatus. Commercially available essays were used: TaqMan SNPs and Universal TaqMan MasterMix Genotyping Assay (Applied Biosystems, USA), according to the manufacturer's protocol. RESULTS: Carriers of DNMT1 genotype variation rs2228612 had a poorer chance of overall survival as well as recurrence-free survival (p = 0.000 and p = 0.000, respectively). DNMT1 rs2228612 was associated with ulceration (p = 0.045), nodal status (p = 0.030), progression (p = 0.007), and disease stage (p = 0.003). Univariate analyzes indicate that tumor infiltrating lymphocytes (TIL) may be markers of good prognosis in patients with melanoma (HR = 0.323, [0.127-0.855] 95% CI, p = 0.025), while the genotypic distribution of DNMT3B rs406193 polymorphisms is significantly related with the presence of TILs (p = 0.012). Multivariate analysis showed that the DNMT1 (rs2228612) allele was an independent prognostic factor in patients with melanoma (HR = 12.126 [2.345-62.715] 95% CI), while DNMT3B (rs2424932) lost its significance as a prognostic factor. CONCLUSION: The results of our studies showed for the first time that the rs2228612 DNMT1 gene polymorphism may be associated with decreased overall survival of melanoma patients. Also, the rs2424932 DNMT3B gene polymorphism showed a strong trend in association with disease progression and risk for shorter overall survival of melanoma patients. The rs406193DNMT 3B gene polymorphism is associated with an increased presence of tumor infiltrating lymphocytes (TIL), which are a good prognostic marker. These findings indicate that further research in this direction could potentially lead to the discovery of new molecular markers and / or new therapies.en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Крагујевцу, Факултет медицинских наукаsr
dc.rightsopenAccessen
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceУниверзитет у Крагујевцуsr
dc.subjectmelanom, polimorfizam, DNA metiltransferazasr
dc.subjectmelanoma, polymorphism, DNA methyltransferaseen
dc.subjectDNMT1en
dc.subjectDNMT3Ben
dc.subjectTILen
dc.subjectsurvivalen
dc.subjectDNMT1sr
dc.subjectDNMT3Bsr
dc.subjectTILsr
dc.subjectpreživljavanjesr
dc.titleUticaj polimorfizama gena za DNA metiltransferaze na tok i ishod melanomasr
dc.title.alternativeThe influence of gene polymorphisms on DNA methyltransferase on melanoma flow and outcomeen
dc.typePhD thesis
dc.rights.licenseBY
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/71003/Disertacija.pdf
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/71004/bitstream_71004.pdf
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_18249


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