{"id":2501,"date":"2022-10-26T12:34:53","date_gmt":"2022-10-26T10:34:53","guid":{"rendered":"https:\/\/www.newslab.sk\/extracelularna-mitochondrialna-dna-ako-neinvazivny-biomarker-nadorovych-ochoreni\/"},"modified":"2022-10-26T12:38:20","modified_gmt":"2022-10-26T10:38:20","slug":"extracelularna-mitochondrialna-dna-ako-neinvazivny-biomarker-nadorovych-ochoreni","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/extracelularna-mitochondrialna-dna-ako-neinvazivny-biomarker-nadorovych-ochoreni\/","title":{"rendered":"Extracellular mitochondrial DNA as a non-invasive biomarker of cancer"},"content":{"rendered":"

*A rare case of autochthonous human dirofilariasis with the manifestation of pseudotumor of the epididymis caused by helminth Dirofilaria repens<\/strong><\/span><\/p>\n

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\u00davod<\/strong><\/p>\n

Mitochondria ako semiauton\u00f3mna organela obsahuje vlastn\u00fd gen\u00f3m v podobe 100 \u2013 10 000 k\u00f3pi\u00ed cirkul\u00e1rnych molek\u00fal mitochondri\u00e1lnej DNA (mtDNA) s d\u013a\u017ekou 16 569 bp, ktor\u00e1 je organizovan\u00e1 do nukleoprote\u00ednov\u00fdch \u0161trukt\u00far (tzv. nukleoidov). Mitochondri\u00e1lny gen\u00f3m je charakteristick\u00fd t\u00fdm, \u017ee nem\u00e1 intr\u00f3ny, no obsahuje 37 g\u00e9nov k\u00f3duj\u00facich 13 polypeptidov d\u00fdchacieho re\u0165azca, 22 tRNA a 2 rRNA. T\u00e1to organela sa podie\u013ea na produkcii energetick\u00fdch metabolitov a molek\u00fal, prostredn\u00edctvom ktor\u00fdch ovplyv\u0148uje d\u00f4le\u017eit\u00e9 bunkov\u00e9 funkcie vr\u00e1tane aktivity enz\u00fdmov, epigenetick\u00fdch modifik\u00e1ci\u00ed \u010di apopt\u00f3zy. Je zrejm\u00e9, \u017ee efektivita t\u00fdchto procesov var\u00edruje pre genetick\u00e9 zmeny v mtDNA, v d\u00f4sledku \u010doho m\u00f4\u017eu vznikn\u00fa\u0165 r\u00f4zne ochorenia, ktor\u00e9 zvy\u010dajne postihuj\u00fa tkaniv\u00e1 s vysok\u00fdmi energetick\u00fdmi po\u017eiadavkami, ako s\u00fa mozog, srdce alebo svaly(1,2). Dysfunkcie mitochondri\u00ed s\u00fa \u010dast\u00e9 aj pri ochoreniach, ako je rakovina. Aber\u00e1cie mtDNA boli identifikovan\u00e9 takmer v ka\u017edom type n\u00e1doru a predpoklad\u00e1 sa, \u017ee by mohli prispieva\u0165 k rozvoju rakovinov\u00e9ho fenotypu. Z\u00e1rove\u0148 v\u0161ak nemo\u017eno vyl\u00fa\u010di\u0165, \u017ee tieto aber\u00e1cie vznikaj\u00fa pr\u00e1ve v d\u00f4sledku rakovinov\u00fdch zmien, ktor\u00e9 prebiehaj\u00fa v n\u00e1dorov\u00fdch bunk\u00e1ch(3). Na objasnenie \u00falohy t\u00fdchto mut\u00e1ci\u00ed v karcinogen\u00e9ze bude potrebn\u00e9 podrobnej\u0161ie \u0161t\u00fadium, no ukazuje sa, \u017ee ich detekcia by mohla by\u0165 potenci\u00e1lnym markerom pre skor\u00fa diagnostiku n\u00e1dorov\u00fdch ochoren\u00ed.<\/p>\n

Je zn\u00e1me, \u017ee n\u00e1dorov\u00e9 bunky uvo\u013e\u0148uj\u00fa svoje nukleov\u00e9 kyseliny do extracelul\u00e1rneho prostredia. K tomuto javu doch\u00e1dza pri bunkovej smrti, ale taktie\u017e prostredn\u00edctvom in\u00fdch biologick\u00fdch mechanizmov, ktor\u00e9 boli podrobnej\u0161ie op\u00edsan\u00e9 v predch\u00e1dzaj\u00facich pr\u00e1cach(4). V\u00fdsledkom je zmes r\u00f4znych typov extracelul\u00e1rnych nukleov\u00fdch kysel\u00edn vr\u00e1tane mtDNA v telov\u00fdch tekutin\u00e1ch, ktor\u00e9 vykazuj\u00fa genetick\u00e9 \u010drty p\u00f4vodn\u00fdch, teda aj rakovinov\u00fdch buniek. Anal\u00fdza t\u00fdchto molek\u00fal, ktor\u00e9 mo\u017eno extrahova\u0165 napr\u00edklad z krvnej plazmy, m\u00e1 preto potenci\u00e1l ako neinvaz\u00edvny pr\u00edstup pre diagnostiku, sledovanie progresie ochorenia \u010di monitorovanie lie\u010dby dan\u00e9ho ochorenia(5).<\/p>\n

Pri anal\u00fdze cirkuluj\u00facej mtDNA (cf-mtDNA) by sa v\u0161ak mali zoh\u013ead\u0148ova\u0165 \u0161trukt\u00farne rozdiely medzi mitochondri\u00e1lnou a jadrovou DNA. Ke\u010f\u017ee mtDNA je mal\u00e1 molekula a nie je chr\u00e1nen\u00e1 hist\u00f3nmi ako jadrov\u00e1 DNA, tak aj fragmenty cf-mtDNA s\u00fa odli\u0161n\u00e9(6). Ve\u013ekos\u0165 fragmentov cf-mtDNA v biologick\u00fdch tekutin\u00e1ch sa pohybuje v\u00e4\u010d\u0161inou v rozsahu 20 a\u017e 80 bp, no bola op\u00edsan\u00e1 aj existencia cel\u00fdch intaktn\u00fdch molek\u00fal cf-mtDNA v \u013eudskej plazme. Na z\u00e1klade zisten\u00fdch poznatkov sa predpoklad\u00e1, \u017ee cirkul\u00e1rny tvar mtDNA m\u00e1 protekt\u00edvny charakter(7). Podobne ako jadrov\u00e1 DNA aj mtDNA m\u00f4\u017ee by\u0165 transportovan\u00e1 pomocou extracelul\u00e1rnych mem- br\u00e1nov\u00fdch vezik\u00fal (EMV)(8). Tieto vezikuly m\u00f4\u017eu obsiahnu\u0165 aj cel\u00fd mitochondri\u00e1lny gen\u00f3m, ktor\u00fd dok\u00e1\u017eu prenies\u0165 do buniek s po\u0161koden\u00fdm metabolizmom, a tak obnovi\u0165 ich metabolick\u00fa aktivitu. Na druhej strane tak\u00fdto horizont\u00e1lny transfer mtDNA pomocou EMV m\u00f4\u017ee prebudi\u0165 dormantn\u00e9 n\u00e1dorov\u00e9 bunky a vyvola\u0165 ich rezistenciu proti terapii(9).<\/p>\n

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Fragment\u00e1cia cf-mtDNA<\/h2>\n

Molekuly cf-mtDNA m\u00f4\u017eu by\u0165 do cirkul\u00e1cie uvo\u013e\u0148ovan\u00e9 akt\u00edvne zo \u017eiv\u00fdch buniek napr. prostredn\u00edctvom exoz\u00f3mov alebo pas\u00edvne prostredn\u00edctvom bunkovej smrti. Pri apopt\u00f3ze buniek nedoch\u00e1dza k poru\u0161eniu mitochondri\u00e1lnej membr\u00e1ny, v d\u00f4sledku \u010doho ost\u00e1va mtDNA intaktn\u00e1. Zatia\u013e \u010do apoptick\u00e1 forma bunkovej smrti je be\u017en\u00e1 v norm\u00e1lnych bunk\u00e1ch, tak pre n\u00e1dorov\u00e9 bunky je charakteristick\u00e1 nekr\u00f3za. Po\u010das nekr\u00f3zy doch\u00e1dza k rozru\u0161eniu mitochondri\u00ed, uvo\u013eneniu mtDNA a n\u00e1sledne k jej degrad\u00e1cii na krat\u0161ie fragmenty (obr\u00e1zok<\/strong> 1<\/strong>). Preto pacienti s rakovinou vykazuj\u00fa krat\u0161iu d\u013a\u017eku cf-mtDNA (109,15 bp) v porovnan\u00ed so zdrav\u00fdmi jedincami (142,62 bp), pri\u010dom d\u013a\u017eka fragmentov navy\u0161e koreluje s n\u00e1dorovou z\u00e1\u0165a\u017eou a relapsom ochorenia. Anal\u00fdza d\u013a\u017ekov\u00e9ho profilu cf-mtDNA by preto mohla sl\u00fa\u017ei\u0165 ako ukazovate\u013e na sledovanie n\u00e1dorovej z\u00e1\u0165a\u017ee a progresie rakoviny(10).<\/p>\n

Spolu s n\u00e1rastom objemu n\u00e1dorovej masy sa zvy\u0161uje \u00farove\u0148 nekr\u00f3zy v n\u00e1dore(11), \u010do vedie k zv\u00fd\u0161eniu zast\u00fapenia cirkuluj\u00facej n\u00e1dorovej DNA (ctDNA) a z\u00e1rove\u0148 poklesu d\u013a\u017eky fragmentov cf-mtDNA. Fragmenta\u010dn\u00fd profil cf-mtDNA predstavuje u\u017eito\u010dn\u00fd parameter na vyhodnotenie n\u00e1dorovej z\u00e1\u0165a\u017ee na z\u00e1klade inverznej korel\u00e1cie medzi objemom n\u00e1dorovej masy a koncentr\u00e1ciou ctDNA. Vyu\u017eitie fragmenta\u010dn\u00e9ho profilu na anal\u00fdzu n\u00e1dorovej z\u00e1\u0165a\u017ee sa potvrdilo aj v pr\u00edpade pacientov s hepatocelul\u00e1rnym karcin\u00f3mom. Priemern\u00e1 d\u013a\u017eka cf-mtDNA fragmentov z krvi pacientov (162,41 bp) bo- la krat\u0161ia ako v kontroln\u00fdch vzork\u00e1ch (173,25 bp). Navy\u0161e fragmenty cf-mtDNA pacientov s percentu\u00e1lnym zast\u00fapen\u00edm ctDNA viac ako 5 % vykazovali priemern\u00fa d\u013a\u017eku 153,62 bp na rozdiel od pacientov so zast\u00fapen\u00edm ctDNA menej ako 5 % s priemernou d\u013a\u017ekou fragmentov cf-mtDNA 164,36 bp(10). Podobne to bolo v \u010fal\u0161ej \u0161t\u00fadii, kde sa vedci zamerali na pacien- tov s karcin\u00f3mom obli\u010diek. Zistili, \u017ee koncentr\u00e1cia cf-mtDNA v plazme mala vy\u0161\u0161ie hodnoty u pacientov s metastatickou formou ochorenia oproti pacientom bez metast\u00e1z a zdrav\u00fdm jedincom, a z\u00e1rove\u0148 u nich pozorovali pokles indexu integrity (pomer dlh\u00fdch a kr\u00e1tkych fragmentov)(12).<\/p>\n

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Mut\u00e1cie v mtDNA<\/h2>\n

Pri zmen\u00e1ch energetick\u00e9ho a biosyntetick\u00e9ho metabolizmu n\u00e1dorov\u00fdch buniek zohr\u00e1vaj\u00fa centr\u00e1lnu \u00falohu mitochondrie. Jednou z typick\u00fdch zmien je tzv. Warburgov efekt (obr\u00e1zok<\/strong> 2<\/strong>), ke\u010f rakovinov\u00e9 bunky namiesto oxidat\u00edvnej fosforyl\u00e1cie (OXPHOS) uprednost\u0148uj\u00fa pri z\u00edskavan\u00ed energie anaer\u00f3bnu glykol\u00fdzu, a to aj v podmienkach s dostato\u010dn\u00fdm mno\u017estvom kysl\u00edka(13). G\u00e9ny, k\u00f3dovan\u00e9 v mtDNA s\u00fa nevyhnutn\u00e9 pre spr\u00e1vny priebeh OXPHOS, a preto mut\u00e1cie v nich m\u00f4\u017eu prispie\u0165 k rozvoju rakovinov\u00e9ho fenotypu buniek. Tieto mut\u00e1cie m\u00f4\u017eu spada\u0165 do dvoch hlavn\u00fdch tried: (1) z\u00e1va\u017en\u00e9 mut\u00e1cie (tumorig\u00e9nne), ktor\u00e9 inhibuj\u00fa OXPHOS, zvy\u0161uj\u00fa produkciu reakt\u00edvnych foriem kysl\u00edka a podporuj\u00fa prolifer\u00e1ciu n\u00e1dorov\u00fdch buniek, a (2) miernej\u0161ie mut\u00e1cie (adapt\u00edvne), ktor\u00e9 umo\u017e\u0148uj\u00fa n\u00e1dorom prisp\u00f4sobi\u0165 sa nov\u00e9mu prostrediu(14). Zatia\u013e, \u010do v ka\u017edej bunke existuje iba jedna k\u00f3pia gDNA, v pr\u00edpade mtDNA ich m\u00f4\u017ee existova\u0165 viacero. V z\u00e1vislosti od \u00farovne metabolickej aktivity m\u00f4\u017ee ma\u0165 bunka stovky mitochondri\u00ed, z ktor\u00fdch ka\u017ed\u00e1 m\u00e1 1 a\u017e 10 k\u00f3pi\u00ed mtDNA. Ak m\u00e1 bunka v\u0161etky k\u00f3pie mtDNA identick\u00e9, hovor\u00edme o tzv. homoplazmii(15). P\u00f4soben\u00edm zv\u00fd\u0161en\u00e9ho oxida\u010dn\u00e9ho stresu spojen\u00fdm so starnut\u00edm doch\u00e1dza k po\u0161kodeniu mtDNA. Nedostato\u010dn\u00e9 repara\u010dn\u00e9 mechanizmy napokon ved\u00fa ku kumu- l\u00e1cii mut\u00e1ci\u00ed mtDNA v bunke(16). Ke\u010f je v jednej bunke zmes mutovanej mtDNA spolu s nemutovanou, nast\u00e1va heteroplazmia(17). Po\u010das bunkov\u00e9ho delenia doch\u00e1dza k n\u00e1hodnej distrib\u00facii heteroplazmatickej mtDNA do dc\u00e9rskych buniek. Bunky m\u00f4\u017eu tolerova\u0165 iba ur\u010dit\u00fa \u00farove\u0148 heteroplazmie, k\u00fdm sa neobjav\u00ed aberantn\u00fd fenotyp(15), ktor\u00fd z\u00e1vis\u00ed od pomeru t\u00fdchto molek\u00fal mtDNA(18). Patog\u00e9nne mut\u00e1cie v mtDNA sa m\u00f4\u017eu vyskytova\u0165 v r\u00f4znych pomeroch a klinick\u00e9 d\u00f4sledky mutovanej mtDNA sa prejavuj\u00fa a\u017e po prekro\u010den\u00ed prahovej hodnoty(19). Uk\u00e1zalo sa, \u017ee heteroplazmia komplikuje detekciu tumorovo \u0161pecifick\u00fdch mut\u00e1ci\u00ed v cf-mtDNA(20,21). Preto ju treba zoh\u013ead\u0148ova\u0165 na intracelul\u00e1rnej aj medzibunkovej \u00farovni(22). Ak sa zd\u00e1, \u017ee mut\u00e1cia detegovan\u00e1 v cf-mtDNA je heteroplaz- matick\u00e1, v skuto\u010dnosti m\u00f4\u017ee by\u0165 v\u00fdsledkom kontamin\u00e1cie mtDNA z r\u00f4znych buniek (medzibunkov\u00e1 heteroplazmia). To vysvet\u013euje, pre\u010do aj zdanlivo n\u00edzka \u00farove\u0148 heteroplazmatickej mut\u00e1cie m\u00f4\u017ee hra\u0165 funk\u010dn\u00fa \u00falohu vo v\u00fdvoji alebo progresii n\u00e1doru na lok\u00e1lnej \u00farovni(20).<\/p>\n

Napriek t\u00fdmto limit\u00e1ci\u00e1m sa ukazuje, \u017ee mut\u00e1cie v cf-mtDNA maj\u00fa potenci\u00e1l ako neinvaz\u00edvny biomarker, ktor\u00fd mo\u017eno vyu\u017ei\u0165 pri predikcii, diagnostike a monitorovan\u00ed n\u00e1dorov\u00fdch ochoren\u00ed. Jeden z pr\u00edkladov m\u00f4\u017ee predstavova\u0165 detekcia mut\u00e1ci\u00ed v cf-mtDNA v oblasti D-slu\u010dky z plazmy pacientov so skvam\u00f3znym karcin\u00f3mom hlavy. Uk\u00e1zalo sa, \u017ee detekcia somatick\u00fdch mut\u00e1ci\u00ed umo\u017e\u0148uje skor\u00e9 zavedenie prevent\u00edvnych opatren\u00ed, preto by cf-mtDNA mohla predstavova\u0165 biomarker v\u010dasnej detekcie ochorenia(23). Liu et al. 2021 predstavil optimalizovan\u00fd pr\u00edstup na b\u00e1ze NGS pre detekciu n\u00e1dorovo \u0161pecifick\u00fdch mut\u00e1ci\u00ed v cf-mtDNA z plazmy pacientov s hepatocelul\u00e1rnym karcin\u00f3mom. Na druhej strane sa mu t\u00fdmto pr\u00edstupom nepodarilo detegova\u0165 mut\u00e1cie u pacientov s kolorekt\u00e1lnym karcin\u00f3mom, \u010do nazna\u010duje \u017ee existuj\u00fa rakovinovo \u0161pecifick\u00e9 rozdiely v mno\u017estve n\u00e1dorovej mtDNA, ktor\u00e1 sa uvo\u013e\u0148uje do plazmy pacientov(24). V\u00fdsledky porovn\u00e1vac\u00edch NGS anal\u00fdz mtDNA s\u00fa limitovan\u00e9 schopnos\u0165ou sledova\u0165 tumorovo \u0161pecifick\u00e9 varianty v cf-mtDNA. V\u00e4\u010d\u0161ina variantov, ktor\u00e9 boli identifikovan\u00e9 v n\u00e1dorovom tkanive, nebola detegovate\u013en\u00e1 v plazme pr\u00edslu\u0161n\u00e9ho pacienta, pri\u010dom zhoda medzi variantmi bola iba na \u00farovni 17 %(21) a\u017e 25 %(25). V s\u00fa\u010dasnosti st\u00e1le nie je jasn\u00e9, pre\u010do je detekcia variantov z plazmatickej cf-mtDNA tak\u00e1 n\u00e1ro\u010dn\u00e1, preto zost\u00e1va jednou z hlavn\u00fdch v\u00fdziev v aplik\u00e1ci\u00e1ch tekutej biopsie.<\/p>\n

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Po\u010det k\u00f3pi\u00ed mtDNA<\/h2>\n

Jedine\u010dn\u00e9 vlastnosti mitochondri\u00e1lneho gen\u00f3mu, ako jeho kr\u00e1tka d\u013a\u017eka, jednoduch\u00e1 molekul\u00e1rna \u0161trukt\u00fara a vysok\u00fd po\u010det k\u00f3pi\u00ed, z neho robia vhodn\u00fd n\u00e1stroj na v\u010dasn\u00fa detekciu n\u00e1dorov\u00fdch ochoren\u00ed(26). Po\u010det k\u00f3pi\u00ed mtDNA je v bunk\u00e1ch r\u00f4znych tkan\u00edv odli\u0161n\u00fd a je v\u00fdznamne ovplyvnen\u00fd aj rozdielnymi podmienkami vn\u00fatorn\u00e9ho a vonkaj\u0161ieho mikroprostredia(27). Na rozdiel od jadrovej DNA je mtDNA extr\u00e9mne n\u00e1chyln\u00e1 na oxida\u010dn\u00e9 a in\u00e9 genotoxick\u00e9 po\u0161kodenia pre nedostatok ochrann\u00fdch hist\u00f3nov a \u00fa\u010dinn\u00fdch mechanizmov opravy DNA(28). Zmeny v po\u010dte k\u00f3pi\u00ed mtDNA boli asociovan\u00e9 s rozvojom r\u00f4znych typov n\u00e1dorov\u00fdch ochoren\u00ed vr\u00e1tane rakoviny hrub\u00e9ho \u010dreva, kone\u010dn\u00edka, prsn\u00edka a p\u013e\u00fac, pri\u010dom tieto zmeny mo\u017eno detegova\u0165 pomocou anal\u00fdzy cf-mtDNA(6). Existuje predpoklad, \u017ee po\u010det k\u00f3pi\u00ed mtDNA v organizme jedinca je ovplyvnen\u00fd \u0161pecifick\u00fdm miestom na mitochondri\u00e1lnom gen\u00f3me, v ktorom vznikla mut\u00e1cia asociovan\u00e1 s konkr\u00e9tnym n\u00e1dorov\u00fdm ochoren\u00edm. Mut\u00e1cie v oblasti D-slu\u010dky zodpovednej za regul\u00e1ciu replik\u00e1cie mtDNA by pod\u013ea tohto predpokladu mali sp\u00f4sobi\u0165 zn\u00ed\u017eenie po\u010dtu k\u00f3pi\u00ed mtDNA v bunke. Naopak, zv\u00fd\u0161en\u00fd po\u010det k\u00f3pi\u00ed mtDNA na bunku m\u00f4\u017ee by\u0165 d\u00f4- sledkom mut\u00e1cie v g\u00e9noch pre prote\u00edny podie\u013eaj\u00face sa na oxida\u010dnej fosforyl\u00e1cii. V tom pr\u00edpade by mohlo \u00eds\u0165 o kompenza\u010dn\u00fd mechanizmus, \u010di\u017ee reakciu na mitochondri\u00e1lnu dysfunkciu(29). Na druhej strane existuj\u00fa aj \u0161t\u00fadie, ktor\u00e9 upozor\u0148uj\u00fa na to, \u017ee somatick\u00e9 mut\u00e1cie v oblasti D-slu\u010dky m\u00f4\u017eu zapr\u00ed\u010dini\u0165 n\u00e1rast po\u010dtu k\u00f3pi\u00ed mtDNA, \u010do by mohlo by\u0165 sp\u00f4soben\u00e9 zv\u00fd\u0161en\u00edm replik\u00e1cie v d\u00f4sledku mut\u00e1cie v tejto oblasti(30). Mechanizmus, prostredn\u00edctvom ktor\u00e9ho m\u00f4\u017ee by\u0165 zn\u00ed\u017een\u00fd po\u010det k\u00f3pi\u00ed mtDNA spojen\u00fd s karcinogen\u00e9zou, nie je \u00faplne jasn\u00fd, no predpoklad\u00e1 sa, \u017ee n\u00edzka hladina fyzickej aktivity u mlad\u00fdch jedincov vedie k zn\u00ed\u017eeniu po\u010dtu k\u00f3pi\u00ed mtDNA a zn\u00ed\u017eenej produkcii ATP, v\u00fdsledkom \u010doho sa zvy\u0161uje riziko rakoviny(31). Tieto v\u00fdsledky nazna\u010duj\u00fa, \u017ee abnorm\u00e1lny po\u010det k\u00f3pi\u00ed mtDNA by mohol sl\u00fa\u017ei\u0165 ako potenci\u00e1lny marker pre po\u0161kodenia DNA a dysfunkciu mitochondri\u00ed, ktor\u00e9 pravdepodobne prispievaj\u00fa ku karcinogen\u00e9ze.<\/p>\n

Zmeny v po\u010dte k\u00f3pi\u00ed cf-mtDNA boli op\u00edsan\u00e9 pri r\u00f4znych typoch n\u00e1dorov\u00fdch ochoren\u00ed (tabu\u013eka 1<\/strong>), preto by kvantifik\u00e1cia cf-mtDNA vo vzork\u00e1ch telov\u00fdch tekut\u00edn mohla posl\u00fa\u017ei\u0165 na rozl\u00ed\u0161enie pacientov s n\u00e1dorov\u00fdm ochoren\u00edm od zdrav\u00fdch jedincov alebo ako marker na monitorovanie progresie n\u00e1doru \u010di predikciu reakcie pacienta na lie\u010dbu(32).<\/p>\n

Zmeny v po\u010dte k\u00f3pi\u00ed mtDNA sa oby\u010dajne po\u010d\u00edtaj\u00fa ako relat\u00edvny pomer mno\u017estva konkr\u00e9tneho g\u00e9nu k\u00f3dovan\u00e9ho mitochondri\u00e1lnym gen\u00f3mom k mno\u017estvu g\u00e9nu k\u00f3dovan\u00e9mu jadrovou DNA. Presnos\u0165 a efektivita tejto met\u00f3dy m\u00f4\u017eu by\u0165 obmedzen\u00e9, \u010do sa m\u00f4\u017ee odzrkadli\u0165 na d\u00f4veryhodnosti v\u00fdsledkov(26). Vari\u00e1cie v po\u010dte k\u00f3pi\u00ed cf-mtDNA sa m\u00f4\u017eu v\u00fdrazne l\u00ed\u0161i\u0165 pri r\u00f4znych typoch n\u00e1dorov\u00fdch ochoren\u00ed. Na overenie presnosti inform\u00e1ci\u00ed o priebehu ochorenia je preto potrebn\u00e9 v\u00fdsledky z\u00edskan\u00e9 z anal\u00fdzy cf-mtDNA vyhodnocova\u0165 spolu s v\u00fdsledkami u\u017e osved\u010den\u00fdch biomarkerov(49).<\/p>\n

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Rozsiahle del\u00e9cie mtDNA<\/h2>\n

V porovnan\u00ed s bodov\u00fdmi mut\u00e1ciami s\u00fa rozsiahle del\u00e9cie v r\u00e1mci mtDNA menej \u010dast\u00e9, zato v\u0161ak v\u00fdraznej\u0161ie prispievaj\u00fa k rozvoju mitochondri\u00e1lnych ochoren\u00ed, rakoviny alebo k st\u00e1rnutiu(50). Ich vplyv na karcinogen\u00e9zu nie je dostato\u010dne objasnen\u00fd a jeho predikt\u00edvny a prognostick\u00fd potenci\u00e1l je st\u00e1le predmetom \u0161t\u00fadia. S viacer\u00fdmi typmi n\u00e1dorov\u00fdch ohoren\u00ed je \u010dasto sp\u00e1jan\u00e1 del\u00e9cia mtDNA 4 977 bp medzi nukleotidmi 8 470 a\u017e 13 447, ktor\u00e1 postihuje d\u00f4le\u017eit\u00e9 g\u00e9ny zodpovedn\u00e9 za spr\u00e1vnu funkciu OXPHOS(51). \u0160t\u00fadia Nie et al. uk\u00e1zala, \u017ee miera t\u00fdchto del\u00e9ci\u00ed bola v\u00fdznamne vy\u0161\u0161ia v krvi pacientov s karcin\u00f3mom prsn\u00edka v porovnan\u00ed s ben\u00edgnym ochoren\u00edm, pri\u013eahl\u00fdm tkanivom, aj so zdrav\u00fdmi kontrolami, \u010do poukazuje na potenci\u00e1l del\u00e9cie mtDNA 4 977 ako neinvaz\u00edvneho biomarkera pre detekciu rakoviny prsn\u00edka(52). Zn\u00e1ma je tie\u017e del\u00e9cia mtDNA 4 576 bp, ktor\u00e1 bola op\u00edsan\u00e1 ako potenci\u00e1lny biomarker pre skr\u00edning rakoviny prsn\u00edka, a to dokonca vo vzork\u00e1ch telov\u00fdch tekut\u00edn(53). Vhodn\u00fdm pr\u00edkladom je aj del\u00e9cia 3397 bp (3.4kb\u0394) v poz\u00edcii 10 743 a\u017e 14 125, ktor\u00e1 je u\u017ei- to\u010dn\u00fdm biomarkerom pre diagnostiku rakoviny prostaty(54). Okrem tkan\u00edv bol presk\u00faman\u00fd potenci\u00e1l tejto del\u00e9cie v mo\u010di a s\u00e9re, no napriek s\u013eubn\u00fdm v\u00fdsledkom je potrebn\u00e9 overi\u0165 vyu\u017eite\u013enos\u0165 tekut\u00fdch biopsi\u00ed na anal\u00fdzu 3.4kb\u0394 na rozsiahlej\u0161\u00edch \u0161t\u00fadi\u00e1ch(55).<\/p>\n

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Mikrosatelitov\u00e1 instabilita mtDNA<\/h2>\n

Mitochondri\u00e1lna mikrosatelitov\u00e1 instabilita (mtMSI) je definovan\u00e1 ako zmena d\u013a\u017eky v r\u00e1mci kr\u00e1tkych tandemov\u00fdch repet\u00edci\u00ed (mikrosatelitov) ve\u013ekosti 1 – 6 bp, pozorovan\u00e1 medzi n\u00e1dorov\u00fdm a zdrav\u00fdm tkanivom. \u010cast\u00e9 vari\u00e1cie v t\u00fdchto lokusoch (del\u00e9cie\/inzercie) vznikaj\u00fa v d\u00f4sledku neefekt\u00edvneho mitochondri\u00e1lneho syst\u00e9mu opravy replika\u010dn\u00fdch ch\u00fdb. Mechanizmy zodpovedn\u00e9 za opravu mtDNA v\u0161ak doposia\u013e nie s\u00fa pr\u00edli\u0161 zn\u00e1me(56). \u010cast\u00fd v\u00fdskyt mtMSI bol op\u00edsan\u00fd v s\u00favislosti s viacer\u00fdmi typmi n\u00e1dorov\u00fdch ochoren\u00ed vr\u00e1tane rakoviny prsn\u00edka, ov\u00e1ri\u00ed, endometria \u010di kolorekt\u00e1lneho karcin\u00f3mu (CRC)(57). V\u00fdskum mtMSI v spojitosti s mo\u017en\u00fdmi klinick\u00fdmi d\u00f4sledkami preuk\u00e1zal, \u017ee pacienti s CRC v III. \u0161t\u00e1diu s mut\u00e1ciami v regi\u00f3ne D-slu\u010dky sa vyzna\u010duj\u00fa zlou progn\u00f3zou a rezistenciou proti adjuvantnej chemoterapii na b\u00e1ze 5-fluorouracilu(58). Pr\u00e1ve vysoko polymorfn\u00e9 oblasti v r\u00e1mci D-slu\u010dky, ak\u00fdmi s\u00fa D310 (poly(C)) a D16184 (poly(C) preru\u0161en\u00e9 T) s\u00fa naj\u010dastej\u0161\u00edmi regi\u00f3nmi, ktor\u00e9 sa sp\u00e1jaj\u00fa s mtMSI(56). Napriek s\u013eubn\u00fdm v\u00fdsledkom pri n\u00e1dorov\u00fdch ochoreniach, mtMSI nebola dostato\u010dne presk\u00faman\u00e1 v telov\u00fdch tekutin\u00e1ch.<\/p>\n

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Epigenetick\u00e9 modifik\u00e1cie mtDNA<\/h2>\n

Podobne ako jadrov\u00e1 tak aj mtDNA je vystaven\u00e1 r\u00f4znym epigenetick\u00fdm modifik\u00e1ci\u00e1m, ktor\u00e9 ovplyv\u0148uj\u00fa d\u00f4le\u017eit\u00e9 procesy ako replik\u00e1cia a transkripcia mtDNA. Dong et al. podrobne op\u00edsal viacer\u00e9 modifik\u00e1cie, medzi ktor\u00e9 patria metyl\u00e1cie a hydroxymetyl\u00e1cie, posttransla\u010dn\u00e9 modifik\u00e1cie prote\u00ednov v mitochondri\u00e1lnych nukleoidoch a tie\u017e posttranskrip\u010dn\u00e9 modifik\u00e1cie mitochondri\u00e1lnych RNA (mtRNA). Boli op\u00edsan\u00e9 aj nek\u00f3duj\u00face RNA odvoden\u00e9 od mtDNA, ktor\u00e9 hraj\u00fa d\u00f4le\u017eit\u00fa \u00falohu pri regul\u00e1cii transl\u00e1cie a funkcie mitochondri\u00e1lnych g\u00e9nov(59). V tejto spojitosti vznikol koncept mitoepigenetiky, ktor\u00e1 \u0161tuduje mitochondri\u00e1lne modifik\u00e1cie ovplyv\u0148uj\u00face dedi\u010dn\u00fd fenotyp bez zmeny samotnej sekvencie mtDNA. Ke\u010f\u017ee dysfunkcie mitochondri\u00ed ako d\u00f4sledok epigenetick\u00fdch zmien m\u00f4\u017eu prispieva\u0165 ku karcinogen\u00e9ze(60), ich anal\u00fdza m\u00e1 potenci\u00e1l pre klinick\u00e9 aplik\u00e1cie v onkol\u00f3gii. Mohd Khair et al. zhrnuli r\u00f4zne typy n\u00e1dorov\u00fdch ochoren\u00ed, ktor\u00e9 boli \u0161tudovan\u00e9 v spojitosti s epigenetick\u00fdmi modifik\u00e1ciami na \u00farovni bunkovej mtDNA a mtRNA(56), av\u0161ak potenci\u00e1l extracelul\u00e1rnych biomarkerov zatia\u013e nebol u onkologick\u00fdch pacientov dostato\u010dne presk\u00faman\u00fd.<\/p>\n

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Z\u00e1ver<\/h2>\n

Pou\u017eitie kvantitat\u00edvnych a kvalitat\u00edvnych charakterist\u00edk cf-mtDNA pre diagnostiku n\u00e1dorov\u00fdch ochoren\u00ed sa v posledn\u00fdch rokoch stalo cie\u013eom z\u00e1ujmu mnoh\u00fdch v\u00fdskumov. Je to najm\u00e4 v\u010faka mo\u017enosti minim\u00e1lne invaz\u00edvneho z\u00e1kroku odobratia vzorky z telov\u00fdch tekut\u00edn a v\u00fdhod\u00e1m, ktor\u00e9 pon\u00faka kompaktn\u00fd mitochondri\u00e1lny gen\u00f3m. Modern\u00e9 pr\u00edstupy umo\u017e\u0148uj\u00fa anal\u00fdzu r\u00f4znych parametrov, ako je detekcia mut\u00e1ci\u00ed, po\u010det k\u00f3pi\u00ed mtDNA \u010di fragmenta\u010dn\u00fd profil cf-mtDNA, ktor\u00e9 je navy\u0161e mo\u017en\u00e9 kombinova\u0165 s cie\u013eom vytvori\u0165 robustnej\u0161\u00ed n\u00e1stroj pre diagnostiku ochorenia. Molekuly cf-mtDNA preuk\u00e1zali diagnostick\u00fa a\/alebo prognostick\u00fa hodnotu pre viacer\u00e9 n\u00e1dorov\u00e9 ochorenia, no ich vyu\u017eite\u013enos\u0165 st\u00e1le var\u00edruje pri r\u00f4znych typoch rakoviny. Aby mohla by\u0165 zaveden\u00e1 do rutinnej praxe, je e\u0161te potrebn\u00e9 pochopi\u0165 jej \u00falohu pri rozvoji n\u00e1dorov\u00e9ho fenotypu a zrealizova\u0165 rozsiahlej\u0161ie \u0161t\u00fadie v kombin\u00e1cii so zaveden\u00fdmi biomarkermi, ktor\u00e9 sa pou\u017e\u00edvaj\u00fa pri mana\u017emente onkopacientov v s\u00fa\u010dasnosti.<\/p>\n

Po\u010fakovanie<\/em><\/strong><\/p>\n

T\u00e1to publik\u00e1cia vznikla v\u010faka podpore v r\u00e1mci Opera\u010dn\u00e9ho programu Integrovan\u00e1 infra\u0161trukt\u00fara pre projekty: ITMS: 313011V446 (40 %); ITMS: 313011V578 (40 %) <\/em>a ITMS: 313011ATL7 (20 %) spolufinancovan\u00e9 zo zdrojov Eur\u00f3pskeho fondu region\u00e1lneho rozvoja.<\/em><\/p>\n

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              10. Sharma N, Pasala MS, Prakash Mitochondrial DNA: Epigenetics and environment. Environ<\/em> Mol<\/em> Mutagen<\/em>. 2019; 60(8): 668-682.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

                *A rare case of autochthonous human dirofilariasis with the manifestation of pseudotumor of the epididymis caused by helminth Dirofilaria repens   \u00davod Mitochondria ako semiauton\u00f3mna organela obsahuje vlastn\u00fd gen\u00f3m v podobe 100 \u2013 10 000 k\u00f3pi\u00ed cirkul\u00e1rnych molek\u00fal mitochondri\u00e1lnej DNA (mtDNA) s d\u013a\u017ekou 16 569 bp, ktor\u00e1 je organizovan\u00e1 do nukleoprote\u00ednov\u00fdch \u0161trukt\u00far (tzv. nukleoidov). Mitochondri\u00e1lny<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[290],"tags":[1755,1930,1933,1932],"class_list":["post-2501","post","type-post","status-publish","format-standard","hentry","category-genetics","tag-biomarker-en","tag-cf-mtdna-en","tag-heteroplasmy","tag-mitochondria-en","typ_clanku-review-article"],"acf":{"abstrakt":"

                Mitochondria play an essential role in the energy metabolism of cells and thus affect essential cellular functions possibly associated with cancer development. Mitochondrial DNA (mtDNA) molecules can be released from cells into the extracellular space by an active or passive mechanism, making them circulating mtDNA (cf-mtDNA). This fact opens up new possibilities for early and non-invasive analysis of the tumour genetic profile from liquid biopsies. Current methods allow the analysis of several parameters, such as tumour-specific mtDNA mutations, mtDNA copy number changes, or different lengths of cf-mtDNA fragments in circulation. Methods of cf-mtDNA analysis are constantly evolving. Thus, implementing the acquired knowledge could be the basis for more effective prevention and overall management of cancer. Although the utility of cf-mtDNA still varies in various types of cancer, and its analysis faces limitations such as heteroplasmy, it can be declared that cf-mtDNA has diagnostic and\/or prognostic potential as a non-invasive biomarker of cancer.<\/p>\n

                Keywords:<\/strong> mitochondria, cf-mtDNA, heteroplasmy, biomarker<\/p>\n","casopis":[{"ID":2437,"post_author":"7","post_date":"2022-10-26 08:29:25","post_date_gmt":"2022-10-26 06:29:25","post_content":"newslab 1\/2022<\/strong>\r\n

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                • Using immunohistochemistry to examine MMR protein expression in endometrial tumours is a suitable method for the primary selection of potential cases with Lynch syndrome<\/li>\r\n \t
                • Metabolomics: a\u00a0potential tool for an individual approach to depressive diseases<\/li>\r\n \t
                • The role of epigenetics in endometrial cancer<\/li>\r\n \t
                • Vaccine vulnerabilities: can we prevent them?\r\n\u2013 SARS-CoV-2 case study<\/li>\r\n<\/ul>","post_title":"newslab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-9","to_ping":"","pinged":"","post_modified":"2022-10-26 08:32:07","post_modified_gmt":"2022-10-26 06:32:07","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.newslab.sk\/casopis\/newslab-9\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"31-36","upload_clanok":{"ID":2495,"id":2495,"title":"NEWSLAB 1-2022_Bokorov\u00e1","filename":"NEWSLAB-1-2022_Bokorova.pdf","filesize":843915,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2022\/10\/NEWSLAB-1-2022_Bokorova.pdf","link":"https:\/\/www.newslab.sk\/en\/extracelularna-mitochondrialna-dna-ako-neinvazivny-biomarker-nadorovych-ochoreni\/newslab-1-2022_bokorova-2\/","alt":"","author":"7","description":"","caption":"","name":"newslab-1-2022_bokorova-2","status":"inherit","uploaded_to":2501,"date":"2022-10-26 09:39:30","modified":"2022-10-26 09:39:30","menu_order":0,"mime_type":"application\/pdf","type":"application","subtype":"pdf","icon":"https:\/\/www.newslab.sk\/wp-includes\/images\/media\/document.png"}},"_links":{"self":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/2501","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/comments?post=2501"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/2501\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=2501"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=2501"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=2501"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}