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Title:Genetski dejavniki tveganja za razvoj miomov maternice
Authors:ID Krsteski, Jovan (Author)
ID Potočnik, Uroš (Mentor) More about this mentor... New window
ID Pakiž, Maja (Comentor)
Files:.pdf DOK_Krsteski_Jovan_2022.pdf (9,85 MB)
MD5: 7340081D32413EA0762923D51F7CBE8A
 
Language:Slovenian
Work type:Doctoral dissertation
Typology:2.08 - Doctoral Dissertation
Organization:MF - Faculty of Medicine
Abstract:Miomi maternice so pogosti trdi tumorji, ki nastanejo v sloju gladkih mišic maternične stene. Njihov nastanek je povezan z motnjami v regulaciji hormonov, vendar je točna etiologija miomov maternice še precej nejasna. Znano je, da na biologijo tumorjev, kot so miomi maternice, pomembno vplivajo interlevkini in interlevkinski receptorji. Dosedanje genetske raziskave miomov maternice so odkrile gene, povezane z etiologijo miomov maternice, vendar so novejši pristopi dodatno izpostavili tudi vlogo patogenih epigenetskih sprememb kot pomemben dejavnik pri napačni regulaciji genskega izražanja v miomih maternice. Na začetku doktorskega dela smo izvedli tarčno analizo izbranih polimorfizmov posameznega nukleotida (SNP) v genih, ki zapisujejo interlevkine in interlevkinske receptorje. Kohorta za tarčno genetsko analizo obsega 181 žensk z miomi maternice in 133 zdravih kontrol. Pri navedeni analizi smo dodatno želeli odkriti razlike med bolnicami s solitarnimi in multiplimi miomi maternice. V nadaljevanju doktorske disertacije smo ponovno analizirali javno dostopne surove podatke določevanja zaporedja RNA (RNA-Seq) iz dveh raziskav miomov maternice, ki so analizirale parne vzorce fibroidnega tumorskega tkiva in tkiva zdravega miometrija. Ta združena podatkovna zbirka je služila za odkritje diferencialnega izražanja in za kasnejše vrednotenje rezultatov. Značilne rezultate te in silico analize smo nato neodvisno potrdili na lastni kohorti, ki je obsegala 58 bolnic z neparnimi vzorci fibroidnega tumorskega tkiva in tkiva zdravega miometrija. Nato smo značilne rezultate še dodatno analizirali na integrirani zbirki podatkov asociacijskih študij celotnega genoma (GWAS) bolnic z miomi maternice za odkritje epigenetskih označevalcev. Rezultati tarčne analize izbranih SNP-jev kažejo na vlogo rs20541 (v genu IL13) pri nastanku miomov maternice. Napovedni model na osnovi logistične regresije je pokazal, da so adenomioza, višja starost ob diagnozi, družinska anamneza, nižja starost ob menarhi in nižja starost pri prvem spolnem odnosu ter SNP rs1801275 (v genu IL4R) povezani s tveganjem za nastanek multiplih miomov maternice. V raziskavi smo prav tako pokazali povezavo med SNP rs20541 (v genu IL13) in ravnjo 17β-estradiola v serumu pri bolnicah z multiplimi miomi maternice. Ponovna in silico analiza podatkov določevanja zaporedja RNA je pokazala značilno diferencialno izražanje genov med zdravim tkivom miometrija in fibroidnim tumorskim tkivom. Izmed teh ima pet genov (NPTX1, NPTX2, CHRM2, DRD2 in CACNA1A) več skupnih značilnih povezav s termini genske ontologije (GO), kar kaže na podobno delovanje teh petih diferencialno izraženih genov. Naštete statistično značilne gene smo tudi potrdili v kohorti slovenskih bolnic. Kasnejša integracija podatkov asociacijskih analiz celotnega genoma in funkcijska analiza naštetih petih genetskih regij je pokazala več pomembnih razlik v vezani kromatinskih struktur, delovanju promotorjev in občutljivosti DNaz ter spremenjenih vezavnih mest transkripcijskih dejavnikov. S tem smo odkrili edinstveno podskupino spremenjenega izražanja genov sinaptične signalizacije v miomih maternice, kar kaže na kompleksnost biologije tumorjev in obsežnost procesov, povezanih s patogenezo miomov maternice.
Keywords:miomi maternice, genotipizacija, izražanje genov, IL13, sinaptično signaliziranje
Place of publishing:Maribor
Year of publishing:2022
PID:20.500.12556/DKUM-81760 New window
COBISS.SI-ID:130052867 New window
Publication date in DKUM:16.11.2022
Views:660
Downloads:77
Metadata:XML RDF-CHPDL DC-XML DC-RDF
Categories:MF
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Licences

License:CC BY-NC-SA 4.0, Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
Link:http://creativecommons.org/licenses/by-nc-sa/4.0/
Description:A Creative Commons license that bans commercial use and requires the user to release any modified works under this license.
Licensing start date:26.05.2022

Secondary language

Language:English
Title:GENETIC RISK FACTORS FOR DEVELOPMENT OF UTERINE LEIOMYOMAS
Abstract:Uterine leiomyomas are common solid tumors, which originate from the smooth muscle layer of the uterine wall. Although uterine leiomyoma formation is linked with hormone dysregulation, their exact etiology remains largely unknown. Studies show that tumor biology of uterine leiomyoma is influenced by interleukins and interleukin receptors. Current genetic analyses of uterine leiomyoma have reported several genes associated with uterine leiomyoma pathogenesis, while recent approaches also highlight the role of epigenetic malfunctions as an important mechanism of gene dysregulation in uterine leiomyoma. At the beginning of this doctoral thesis, we performed a targeted analysis of selected single nucleotide polymorphisms (SNP) in genes which encode interleukins and interleukin receptors. The cohort for the targeted analysis included 181 females with uterine leiomyoma and 133 healthy controls. In this analysis we additionally aimed to find differences between patients with solitary and multiple uterine leiomyoma. Follow this analysis we conducted an in silico reanalysis of raw RNA sequencing data (RNA-seq) of two publicly available uterine leiomyoma studies with paired samples of fibroid tumor tissue and healthy myometrium. This combined database was used for biomarker discovery and later as a validation set. Significant results of the in silico reanalysis were validated on a second cohort of 58 patients with not-paired-matched samples of fibroid tumor tissue and healthy myometrium. Furthermore, significant results were reanalyzed on an integrated database of uterine leiomyoma genome-wide association studies (GWAs) of to discover novel epigenetic markers. Results of the targeted genetic analysis of selected SNP shows an association between rs20541 (in gene IL13) and uterine leiomyoma pathogenesis. Predictive logistic regression analysis showed that adenomyosis, higher age at diagnosis, family history of uterine leiomyoma occurrence, earlier menarche, lower number of pregnancies and lower age at first sexual intercourse as well as the SNP rs1801275 (in gene IL4R) were associated with an increased risk of multiple uterine leiomyoma. We also found an association between rs20541 and 17β-estradiol serum levels in patients with multiple uterine leiomyoma. The in silico reanalysis of RNA-seq data revealed several differentially expressed genes between healthy myometrium and fibroid tumor tissue samples. Among these results, five genes (NPTX1, NPTX2, CHRM2, DRD2 and CACNA1A) have common statistically significant connections with gene ontology (GO) terms, which indicates common functions of these differentially expressed genes. The five statistically significant genes were further replicated in our cohort. Additional integration of GWAs data and functional analysis showed that genetic variants in these five gene regions are listed at a chromatin structure and state, predicting promoters, enhancers, DNase hypersensitivity and altered transcription factor binding sites. Thus, we identified a unique subgroup of dysregulated synaptic signaling genes in uterine leiomyoma, which adds to the complexity of tumor biology and the extent of biological processes involved in uterine leiomyoma pathogenesis.
Keywords:uterine leiomyomas, genotyping, gene expression, IL13, synaptic signaling


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