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Promotor hypermethyation of BRCA1, p16, MGMT, RASSF1 and CDH-1 genes in correlation with clinical course of disease in estrogen receptor, progesterone receptor and her-2 receptor negative breast cancer

dc.contributor.advisorDžodić, Radan
dc.contributor.otherBranković Magić, Mirjana
dc.contributor.otherTatić, Svetislav
dc.contributor.otherPlešinac Karapandžić, Vesna
dc.contributor.otherŠušnjar, Snežana
dc.creatorKozomara, Zoran B.
dc.date.accessioned2019-02-26T11:22:28Z
dc.date.available2019-02-26T11:22:28Z
dc.date.issued2018-09-25
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=6608
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:19406/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=50791951
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/10772
dc.description.abstractTrostruko-negativni karcinom dojke (engl. triple-negative breast cancer –TNBC) predstavlja subtip karcinoma dojke koji zauzima 15-20% od svih karcinoma dojke, karakteriše se odsustvom receptora za ER i PR, kao i odsustvom povećane ekspresije Her-2 receptora. Kao posledica agresivnog tumorskog fenotipa, nemogućnosti sprovođenja ciljane antitumorske terapije zbog odsustva pomenutih receptora, kao i parcijalnog odgovora na hemioterapije koje se primenjuju za karcinom dojke, ovaj subtip ima lošu prognozu. Intenzivno se izučavaju molekulske mete za praćenje kliničkog toka bolesti i efekata antitumorke terapije. Epigenetičke promene igraju isto tako značajnu ulogu u nastanku kancera kao i promene koje se odvijaju u nivou gena. Cilj ovog rada je bio da se utvrdi da li metilacioni status promotora ispitivanih BRCA1, p16, O6MGMT, RASSF1 i CDH-1 gena kod bolesnica sa trostruko negativnim karcinomom dojke, kao prognostički najlošijom grupom karcinoma dojke sa agresivnim fenotipom, može da se poveže sa kliničkim tokom bolesti i da posluži kao eventualni pokazatelj prognoze bolesti. Materijal i metode: U rad je uključena 131 bolesnica sa karcinomom dojke koje su na početku lečenja bile podvrgnute hirurškom lečenju (61 sa trostruko negativnim karcinomom dojke, a drugu grupu čini 70 bolesnica koje spadaju u najbolju prognostičku grupu karcinoma dojke (ER+, PR+, Her2-). Bolesnice su praćene između 1 i 87 meseci (medijana 78 meseci). Hipermetilacioni status promotorskog regiona BRCA1, p16, O6MGMT, RASSSF1 i CDH-1 gena je određivan u tumorskom tkivu, obzirom da je metilacija tkivno i tumor specifična. DNK iz uzoraka sveže smrznutog tumorskog tkiva je izolovana metodom isoljavanja. Određivanje hipermetilacije promotora specifičnih gena je urađeno metilaciono-specifičnim PCR metodom. Rezultati: Poređenje hipermetilacije promotora BRCA1, p16, O6MGMT, RASSF1 i CDH-1 gena pokazalo je da se ove dve grupe statistički značajno razlikuju samo u odnosu na učestalost hipermetilacije promotora p16 gena – statistički značajno veći broj hipermeilacija promotora gena pronađen je u grupi trostruko negativnog karcinoma dojke, 33 (54.1%) vs. 20 (28.6%), p=0.00298. Iako nije pokazana statistički značajna razlika u učestalosti hipermetilacije promotora BRCA1 gena između ispitivanih grupa bolesnica, uočen je trend ka većem broju hipermetilacija u trostruko negativnom karcinomu dojke grupi bolesnica: 33 (54.1%) prema 27 (38.6%), χ2 test, p=0.0752...sr
dc.description.abstractriple-negative breast cancer, present with frequency of about 15-20% of all breast cancers, is characterized with the lack of estrogen, progesterone and Her-2 receptors and aggressive form of disease. As the consequence of aggressive tumor phenotype, lack of targeted anticancer therapy due to the absence of biological markers, as well as poor response to conventional chemotherapy, triple-negative breast cancer is associated with poor prognosis. Molecular targets that can serve as prognostic as well as predictive markers are intensively studied. It has been proposed that epigenetic changes in the cancer development are as significant as genetic changes. Aim: This work was done in order to evaluate if methylation status of BRCA1, p16, MGMT, RASSF1 and CDH-1 genes in triple-negative brast cancer as prognostically the worst subtype of breast cancer, can be correlated with clinical course and can serve as prognostic markers of disease. Material and Methods: 131 breast cancer patients with surgery as primary treatment were included: 61with triple-negative breast cancer (TNBC) and 70 with estrogen, progesterone positive and Her2 negative (ER+, PR+, Her2- ) breast cancer that represents prognostically the best subtype of breast cancer. The pateints were followed up between 1 and 87 months (median 78 months). Status of promotor hypermethylation of BRCA1, p16, O6MGMT, RASSSF1 i CDH-1 genes was determined in the tumor tissue since methylation is tissue and tumor specific. DNA was isolated from fresh frozen tissues by salting out procedure. Status of promotor hypermethylation was determined by methylation-specific PCR. Results: There was statistically significant difference only in p16 hypermethylated breast cancer cases when TNBC was compared with ER+PR+Her2- group, 33 (54.1%) vs. 20 (28.6%), p=0.00298. Although the difference between the incidences of BRCA1 hypermethylation between the examined groups of patients did not reach statistical significance, we observed a tendency towards higher occurrence of BRCA1 hypermethylation in TNBC compared to ER+PR+Her2- cases: 33 (54.1%) vs. 27 (38.6%), p=0.0752. When the frequencies of co-methylated (combined hypermethylation of the examined genes) p16 and RASSF1A genes (p16+RASSF1A+) were compared between the breast cancer patients with TNBC and ER+PR+Her2- characteristics, we found that the number of patients with both hypermethylated genes was significantly higher in the TNBC than in ER+PR+Her2- group: 20 (32.8%) vs. 10 (14.3%), p=0.0225...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Медицински факултетsr
dc.rightsAutorstvo-Nekomercijalno-Bez prerade 3.0 Srbija (CC BY-NC-ND 3.0)
dc.sourceУниверзитет у Београдуsr
dc.subjectkarcinom dojke, epigenetičke promene, hipermetilacija, BRCA1, p16, MGMT, RASSF1 i CDH-1sr
dc.subjectbreast cancer, epigenetic changes, hypermethylation, BRCA1, p16, MGMT, RASSF1 i CDH-1en
dc.titlePovezanost hipermetilacije promotora BRCA1, p16, MGMT, RASSF1 i CDH-1 gena i toka bolesti bolesnica sa estrogen-receptor, progesteron-receptor i her-2 receptor negativnim karcinomom dojkesr
dc.title.alternativePromotor hypermethyation of BRCA1, p16, MGMT, RASSF1 and CDH-1 genes in correlation with clinical course of disease in estrogen receptor, progesterone receptor and her-2 receptor negative breast canceren
dc.typePhD thesis


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