Klinička važnost izražaja metiltransferaze EZH2 i demetilaze histona H3 JMJD3 u karcinomima pločastih stanica hipofarinksa [Clinical Significance of Methyltransferase EZH2 and Demethylase JMJD3 Expression in Malignant Hypopharyngeal Tumors]

Pegan, Alan (2017) Klinička važnost izražaja metiltransferaze EZH2 i demetilaze histona H3 JMJD3 u karcinomima pločastih stanica hipofarinksa [Clinical Significance of Methyltransferase EZH2 and Demethylase JMJD3 Expression in Malignant Hypopharyngeal Tumors]. PhD thesis, Sveučilište u Zagrebu.

PDF Download (2MB)

Abstract

Hypopharyngeal carcinomas account for 10% of all head and neck tumors. The highest incidence of this tumor is recorded in older population, in which it is commonly presented in an advanced stage. It has been known that these tumors contain multiple genetic abnormalities. This research was focused on investigating the relevance of expression of two epigenetic modulators with antagonistic functions on H3K27, EZH2 and JMJD3, in a setting of a clinical features of the tumor and survival in a cochort of 68 patients. Both, EZH2 and JMJD3, were explored at the level of mRNA and protein. The expression of p53 was determined at the protein level by immunohistochemistry, joined with analyses at the level of genomic DNA (loss of heterozygosity). Kaplan Maier method was used for analysis of overall survival in relation to standard clinical data (age, size of the tumor, presence of lymph node metastases, tumor grade) and expression of the target proteins (EZH2, JMJD3 and p53). The difference between survival curves was tested with Gehan-Wilcoxon test. The 2 test was used for determine whether there is a significant difference between the expected frequencies related to standard clinical features of the tumor. Multivariate analysis based on recursive partitioning was presented as the hazard ratio. The most important clinical parameters for survival of this patient cohort are age and the lymph node status. Although not shown as independent prognostic factors for survival, the high expression of JMJD3 and p53 was significantly associated with the tumor size (JMJD3) and the status of lymph nodes (p53), in univariate analysis. An unexpected phenomenon has been presented in a high proportion of samples, by discovery of unchanged EZH2 expression when tumor and non-tumor tissues were compared. At the same time, JMJD3 was significantly increased in the tumor tissue (when compared to non-tumorous tissue). On a protein level, EZH2 expression decreases the hazard ratio in a subgroup of patients younger than 56,5 years with affected lymph nodes (cN2/cN3) (hazard ratio 0,54 (EZH21-3) vs 1,59 (EZH2 0), in relation to the whole cohort). This discovery profiles EZH2 as the third factor (after the age and lymph node involvement) involved in determination of the hazard ratio for these patients.

Abstract in Croatian

Karcinomi hipofarinksa čine 10% tumora glave i vrata. Najčešće se pojavljuju u starijoj životnoj dobi i otkrivaju u uznapredovalom stadiju bolesti. Poznato je da se u njima nalaze višestruke genetičke promjene. Ovim smo istraživanjem ispitali značaj izraženosti epigenetičkih modulatora metilacije lizina 27 u histonu H3, antagonista EZH2 i JMJD3, u odnosu na kliničke osobitosti tumora i preživljenje 68 bolesnika. Istraživanje za ova dva gena napravljeno je na razini mRNA i proteina. Određen je i izražaj gena TP53 metodom imunohistokemije (protein), združeno s određivanjem gubitka heterozigotnosti (analiza na razini DNA). Preživljenje u odnosu na pojedinačne parametre (starost bolesnika, veličina tumora, zahvaćenost limfnih čvorova, gradus, izražaj EZH2, JMJD3 i p53) prikazan je postupkom po Kaplan-Meieru, a razlika među krivuljama je testirana uporabom testa Gehan-Wilcoxon. Testom -kvadrat su testirane razlike između podataka dobivenih prebrojavanjem. Multivarijatna analiza povezanosti promatranih varijabli s ishodom bolesti zasnivala se na rekurzivnom particioniranju, rezultat kojeg se izrazio kao omjer hazarda. Najznačajniji klinički parametri u procjeni preživljenja su dob i status limfnih čvorova. Iako niti jedan od ciljnih proteina nije pokazan kao neovisni prognostički čimbenik preživljenja, u univarijatnoj analizi je izraženost JMJD3 i p53 bila značajno povezana s veličinom tumora (JMJD3) i statusom limfnih čvorova (p53). Neočekivan rezultat je otkriće relativno stabilne transkripcije EZH2 u tumoru u odnosu na tkivo netumora, praćeno snažnim porastom izražaja JMJD3, u tkivu tumora. Izražaj EZH2 smanjuje omjer hazarda u podskupini bolesnika mlađih od 56,5 godina sa statusom limfnih čvorova cN2/cN3 (omjer hazarda: 0,54 (EZH 2 1-3) vs 1,59 (EZH2 0), u odnosu na sve oboljele), čime postaje treća varijabla (nakon dobi i statusa limfnih čvorova) koja određuje omjer hazarda za preživljenje ovih bolesnika.

Actions (login required)

View Item

Downloads