Dna methylation in carcinogenesis

Nastanak karcinoma podrazumijeva inaktivaciju gena za tumorske supresore i aktivaciju protoonkogena, što za posljedicu ima pojavu obilježja malignih tumora koja uključuju neograničen i nekontroliran rast i dijeljenje stanica, sposobnost invazije u okolna tkiva, formiranje metastaza te indukciju angiogeneze. U karcinogenezi osim mutacija u DNA jednak značaj imaju i epigenetički mehanizmi. U stanju homeostaze u stanici prevladava ravnoteža između metilacije i demetilacije DNA, dok je u tumorima primijećena globalna hipometilacija genoma te lokalna hipometilacija u odnosu na neizmijenjene stanice. Lokalna hipermetilacija najčešće se događa u promotorskim regijama i povezana je s inaktivacijom gena, a globalna hipometilacija doprinosi kromosomskoj nestabilnosti koja dovodi do kromosomskih rearanžmana koji uključuju aneuploidije, translokacije i delecije. 5-metilcitozin pospješuje nastanak točkastih mutacija spontanom deaminacijom posredujući pritom u tranziciji citozina u timin. Osim inaktivacije gena metilacijom, po stanicu je jednako nepovoljna aktivacija utišanih gena demetilacijom. Na primjerima proteina p16-INK4a, p14ARF, p53, pVHL i heparanaze prikazana je umreženosti staničnih procesa čiji poremećaji dovode do nastanka tumora i doprinose malignosti. Cilj ovog rada bio je prikazati obilježja metilacije DNA i njezin utjecaj na genom te na primjerima poznatih promjena u statusu metilacije u karcinomima ukazati na važnost metilacije kao pokretača malignih promjena, ali i na potencijal koji posjeduje za dijagnostičke i terapijske svrhe.Carcinoma development includes tumour suppressor gene inactivation and proto-oncogene activation which provide the tumour with malignant characteristics such as unlimited and unregulated cell growth and division, ability to invade surrounding tissues and form mestastasis as well as to induce angiogenesis. Epigenetic mechanisms in carcinogenesis are equally important as mutations in DNA. In homeostasis there is a balance between DNA methylation and demethylation within a cell, while in tumour cells global hypomethilation and local hypermethyilation have been observed. Local hypermethyilation most commonly affects promoter regions and is associated with gene inactivation while global hypomethilation contributes to chromosomal instability as it is associated with chromosomal rearangements which lead to aneuplody, translocations and deletions. Moreover, 5-methylcytosine increases the rate of point mutations for spontaneous deamination and causes cytosine to tymine transversions. Both methylation driven gene inactivation and demethylation of silenced genes represent risk for tumour development. The role of p16-INK4a, p14ARF, p53, pVHL proteins and heparanase illustrate the complexity of cellular processes whose dysregulation leads to tumorigenesis and affect the malignancy. The aim of this work was to show the characteristics of DNA methylation and consequential effects on the genome, as well as to emphasize the importance of DNA methylation in carcinogenesis. Using known examples of DNA methylation changes in carcinoma, the aim was to show its potential as diagnostic and prognostic marker