{"id":2279,"date":"2021-09-20T10:30:08","date_gmt":"2021-09-20T08:30:08","guid":{"rendered":"https:\/\/www.newslab.sk\/detekcia-mikrosatelitnej-instability-v-nadoroch-asociovanych-s-lynchovym-syndromom\/"},"modified":"2021-09-20T10:31:57","modified_gmt":"2021-09-20T08:31:57","slug":"detection-of-microsatellite-instability-in-lynch-syndrome-associated-tumours","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/detection-of-microsatellite-instability-in-lynch-syndrome-associated-tumours\/","title":{"rendered":"Detection of microsatellite instability in Lynch syndrome-associated tumours"},"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

 <\/p>\n

Lynchov syndr\u00f3m je autozom\u00e1lne dominantn\u00e9 dedi\u010dn\u00e9 ochorenie charakterizovan\u00e9 defektmi v syst\u00e9me opravy chybne sp\u00e1rovan\u00fdch b\u00e1z \u2013 MMR syst\u00e9me (mismatch <\/em>repair system<\/em>). Ide o postreplikat\u00edvny opravn\u00fd syst\u00e9m zais\u0165uj\u00faci integritu gen\u00f3mu prostredn\u00edctvom repar\u00e1cie chybne inkorporovan\u00fdch nukleotidov, tvoren\u00fd predov\u0161etk\u00fdm \u0161tyrmi hlavn\u00fdmi g\u00e9nmi MLH1<\/em>, MSH2<\/em>, MSH6 <\/em>a PMS2. <\/em>Je zn\u00e1me, \u017ee pacienti s diagnostikovan\u00fdm Lynchov\u00fdm syndr\u00f3mom s\u00fa vystaven\u00ed zv\u00fd\u0161en\u00e9mu riziku rozvoja viacn\u00e1sobn\u00fdch synchr\u00f3nnych alebo metachr\u00f3nnych kolonick\u00fdch a\/alebo extrakolonick\u00fdch malign\u00edt so v\u010dasn\u00fdm n\u00e1stupom fenotypu. U pacientov s Lynchov\u00fdm syndr\u00f3mom sa tieto typy malign\u00edt objavuj\u00fa pomerne skoro, a to priemerne okolo 40. a\u017e 50. roku \u017eivota (tabu\u013eka 1)<\/strong>. Medzi naj\u010dastej\u0161ie typy n\u00e1dorov asociovan\u00fdch s Lynchov\u00fdm syndr\u00f3mom patr\u00ed kolorekt\u00e1lny karcin\u00f3m, a to pri oboch pohlaviach, a karcin\u00f3m endometria u \u017eien, ale aj rakovina \u017eal\u00fadka, ov\u00e1ri\u00ed, tenk\u00e9ho \u010dreva, hepatobili\u00e1rneho a urin\u00e1rneho traktu, mozgu a CNS a tie\u017e \u0161irok\u00e9 spektrum \u010fal\u0161\u00edch onkologick\u00fdch ochoren\u00ed(1)<\/a>.<\/p>\n

 <\/p>\n

Mikrosatelity a ich instabilita u pacientov s Lynchov\u00fdm syndr\u00f3mom<\/h3>\n

Mikrosatelity alebo aj kr\u00e1tke tandemov\u00e9 repet\u00edcie (STR; short tandem repeats<\/em>) s\u00fa vo v\u0161eobecnosti definovan\u00e9 ako sekven\u010dn\u00e9 opakovania a\u017e do d\u013a\u017eky 100 b\u00e1zov\u00fdch p\u00e1rov(2). S\u00fa tvoren\u00e9 opakuj\u00facimi sa sekvenciami pozost\u00e1vaj\u00facimi z mot\u00edvov ve\u013ekosti 1 \u2013 6 nukleotidov, pri\u010dom pokr\u00fdvaj\u00fa zhruba 2,5 % \u013eudsk\u00e9ho gen\u00f3mu s po\u010dtom ~ 2,5 mili\u00f3na lokusov(3)<\/a>. S\u00fa ozna\u010dovan\u00e9 za genetick\u00e9 hotspoty <\/em>s mierou mutability 10- a\u017e 100 000\u00d7 vy\u0161\u0161ou v porovnan\u00ed so zvy\u0161kom gen\u00f3mu(4)<\/a>. Ud\u00e1van\u00e1 frekvencia mut\u00e1ci\u00ed na gener\u00e1ciu je oproti jednonukleotidov\u00fdm polymorfizmom r\u00e1dovo vy\u0161\u0161ia(5)<\/a>. Predpoklad\u00e1 sa, \u017ee vari\u00e1cie d\u013a\u017eky STR oblast\u00ed s\u00fa podmienen\u00e9 prek\u013aznutiu DNA v procese replik\u00e1cie, \u010do v kone\u010dnom d\u00f4sledku vedie k indelom ve\u013ekosti jedn\u00e9ho alebo viacer\u00fdch mikrosatelitn\u00fdch mot\u00edvov. Vzniknut\u00e9 indely s\u00fa v oblastiach mikrosatelitn\u00fdch lokusov opravovan\u00e9 najm\u00e4 funk\u010dn\u00fdm MMR syst\u00e9mom(6)<\/a>. Ke\u010f\u017ee mikrosatelity predstavuj\u00fa ve\u013emi nestabiln\u00e9 \u010dasti gen\u00f3mu, pr\u00edtomnos\u0165 patologick\u00fdch z\u00e1rodo\u010dn\u00fdch mut\u00e1ci\u00ed v MMR <\/em>g\u00e9noch a n\u00e1sledn\u00e1 dysfunkcia MMR opravn\u00e9ho syst\u00e9mu u pacientov s Lynchov\u00fdm syndr\u00f3mom m\u00f4\u017eu vy\u00fasti\u0165 do mikrosatelitnej instability (MSI, microsatellite<\/em> instability<\/em>) (obr\u00e1zok 1)<\/strong>, pri\u010dom jej detekcia predstavuje v klinickej praxi d\u00f4le\u017eit\u00fd prognostick\u00fd a diagnostick\u00fd marker.<\/p>\n

<\/h3>\n

Aktu\u00e1lne skr\u00edningov\u00e9 pr\u00edstupy detekcie MSI v klinickej praxi<\/h3>\n

Detekcia MSI a skr\u00edning pacientov s Lynchov\u00fdm syndr\u00f3mom s\u00fa zalo\u017een\u00e9 na dvoch z\u00e1kladn\u00fdch pr\u00edstupoch. Prv\u00fd, vych\u00e1dzaj\u00faci z imunohistoch\u00e9mie (IHC; immunohistochemistry<\/em>) prote\u00ednov zahrnut\u00fdch v MMR syst\u00e9me, a druh\u00fd, vyu\u017e\u00edvaj\u00faci PCR amplifik\u00e1ciu vybran\u00e9ho po\u010dtu mikrosatelitov\u00fdch markerov (MSI-PCR) (tabu\u013eka 2)<\/strong>. Detekcia MSI predstavuje skr\u00edningov\u00fd test, ktor\u00fd umo\u017e\u0148uje z pomerne rozsiahlej vzorky n\u00e1dorov vybra\u0165 tie, ktor\u00e9 m\u00f4\u017eu by\u0165 asociovan\u00e9 s Lynchov\u00fdm syndr\u00f3mom. Uv\u00e1dza sa, \u017ee MSI vykazuje ~ 90 % Lynchov\u00fdch asociovan\u00fdch n\u00e1dorov v porovnan\u00ed s ~ 15 % sporadick\u00fdch kolorekt\u00e1lnych karcin\u00f3mov, sp\u00f4soben\u00fdch najm\u00e4 hypermetyl\u00e1ciou prom\u00f3tora g\u00e9nu MLH1<\/em>(7)<\/a>. Vhodn\u00fdm markerom na selekciu sporadick\u00fdch n\u00e1dorov je vy\u0161etrenie na pr\u00edtomnos\u0165 dan\u00fdch metyl\u00e1ci\u00ed MLH1 <\/em>alebo anal\u00fdza mut\u00e1cie p. V600E v g\u00e9ne BRAF<\/em>(8)<\/a>.<\/p>\n

Met\u00f3da MSI-PCR kombinuje fluorescen\u010dn\u00fa multiplex PCR a kapil\u00e1rov\u00fa elektrofor\u00e9zu, \u010d\u00edm umo\u017e\u0148uje detegova\u0165 status MSI porovn\u00e1van\u00edm fragmenta\u010dn\u00e9ho profilu amplifikovan\u00fdch markerov medzi zdrav\u00fdm a n\u00e1dorov\u00fdm tkanivom z\u00edskan\u00fdm od toho ist\u00e9ho pacienta. V priebehu dek\u00e1d boli predstaven\u00e9 viacer\u00e9 panely, s\u00fa\u010dasn\u00e9 testy \u0161iroko vyu\u017e\u00edvan\u00e9 v klinickej diagnostike sa v\u0161ak spoliehaj\u00fa predov\u0161etk\u00fdm na lokusy tvoren\u00e9 mononukleotidov\u00fdmi opakovaniami \u2013 homopolym\u00e9rmi. V s\u00fa\u010dasnosti najpou\u017e\u00edvanej\u0161ou esejou zalo\u017eenou na tomto princ\u00edpe je met\u00f3da fragmenta\u010dnej anal\u00fdzy MSI Analysis System verzia 1.2 (Promega), ktor\u00e1 vyu\u017e\u00edva panel 5 kv\u00e1zi-monomorfn\u00fdch homopolym\u00e9rnych markerov BAT-25, BAT-26, NR- 21, NR-24 a MONO-27(9)<\/a>.<\/p>\n

Na druhej strane IHC sa odpor\u00fa\u010da ako prvotn\u00e9 skr\u00edningov\u00e9 vy\u0161etrenie pri lie\u010dbe pacientov, u ktor\u00fdch existuje podozrenie na pr\u00edtomnos\u0165 mut\u00e1ci\u00ed v MMR <\/em>g\u00e9noch, s cie\u013eom identifikova\u0165 pacientov, ktor\u00ed s\u00fa vhodn\u00ed na \u010fal\u0161ie molekul\u00e1rnogenetick\u00e9 anal\u00fdzy. IHC predstavuje r\u00fdchlu a relat\u00edvne jednoduch\u00fa esej, ktor\u00e1 deteguje expresiu MMR prote\u00ednov MLH1, PMS2, MSH2 a MSH6 v tkanive odobrat\u00e9ho z reprezentat\u00edvnej \u010dasti biopsie(10)<\/a>. V\u00fdraznej\u0161ou limit\u00e1ciou IHC je nevyhnutn\u00e1 pr\u00edtomnos\u0165 vysokokvalifikovan\u00e9ho person\u00e1lu, a to pri odbere biopsie<\/p>\n

aj pri vyhodnocovan\u00ed anal\u00fdz. Bolo pozorovan\u00e9, \u017ee medzi v\u00fdsledkami MSI a IHC anal\u00fdzami existuje nes\u00falad, pri\u010dom uv\u00e1dzan\u00e1 citlivos\u0165 IHC pri predpovedan\u00ed MSI je ~ 92 %(11,12)<\/a>. Negat\u00edvami IHC s\u00fa takisto falo\u0161ne pozit\u00edvne v\u00fdsledky, ktor\u00e9 vznikaj\u00fa pri tak\u00fdch mut\u00e1ci\u00e1ch v MMR <\/em>g\u00e9noch, ktor\u00e9 vo v\u00fdsledku neovplyv\u0148uj\u00fa transl\u00e1ciu, stabilitu a antigenicitu prote\u00ednu, \u010d\u00edm doch\u00e1dza k jeho intaktn\u00e9mu zafarbeniu(12)<\/a>. Porovnanie technick\u00fdch a metodologick\u00fdch aspektov MSI-PCR a IHC aj ich limit\u00e1cie sumarizuje tabu\u013eka 2<\/strong>.<\/p>\n

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MSI ako indik\u00e1tor progn\u00f3zy odpovede na imunoterapiu<\/h3>\n

Okrem in\u00e9ho detekcia MSI pom\u00e1ha pri selekcii pacientov na zaradenie na imunoterapiu. Preuk\u00e1zalo sa, \u017ee pri metastatickom kolorekt\u00e1lnom karcin\u00f3me je ~ 10 % pacientov nespr\u00e1vne zaraden\u00fdch do imunoterapeutick\u00fdch \u0161t\u00fadi\u00ed v d\u00f4sledku falo\u0161ne pozit\u00edvnych v\u00fdsledkov IHC alebo MSI-PCR(13)<\/a>. Na pos\u00fadenie adekv\u00e1tnosti lie\u010dby pomocou inhib\u00edtorov imunitn\u00e9ho kontroln\u00e9ho bodu (ICI; immune checkpoint inhibitors<\/em>) sa odpor\u00fa\u010da kombin\u00e1cia pr\u00edstupu IHC a MSI-PCR pri metastatickom CRC aj pri in\u00fdch druhoch n\u00e1dorov spadaj\u00facich do spektra Lynchovho syndr\u00f3mu(14)<\/a>. Preuk\u00e1zalo sa, \u017ee n\u00e1dory s vysok\u00fdm stup\u0148om MSI maj\u00fa vo v\u0161eobecnosti vysok\u00fa pravdepodobnos\u0165 reakcie na inhib\u00edciu PD-1\/PD-L1 dr\u00e1hy (programmed cell death 1<\/em>\/programed cell death ligand 1)<\/em>, ktor\u00e1 je pova\u017eovan\u00e1 za jeden z kontroln\u00fdch bodov imunitnej odpovede. Prote\u00edn PD-1, vysokoexprimovan\u00fd aktivovan\u00fdmi T-bunkami, B-bunkami, dendritick\u00fdmi bunkami a NK bunkami, ktor\u00fd po v\u00e4zbe na PD-L1 receptor, nach\u00e1dzaj\u00faci sa vo ve\u013ekom mno\u017estve na niektor\u00fdch rakovinov\u00fdch bunk\u00e1ch, pom\u00e1ha tak\u00fdmto bunk\u00e1m unikn\u00fa\u0165 pred imunitn\u00fdm syst\u00e9mom hostite\u013ea. Monoklon\u00e1lne protil\u00e1tky, ak\u00fdmi s\u00fa inhib\u00edtory anti-PD-1 alebo anti-PD-L1 m\u00f4\u017eu tak\u00fato v\u00e4zbu blokova\u0165 a zvy\u0161ova\u0165 tak imunitn\u00fa odpove\u010f proti bunk\u00e1m n\u00e1doru (obr\u00e1zok 2)<\/strong>. Na z\u00e1klade predklinick\u00fdch \u0161t\u00fadi\u00ed je tento typ lie\u010dby \u00fa\u010dinn\u00fd v kombi- n\u00e1cii s r\u00e1dioterapiou, chemoterapiou, inhib\u00edtormi kin\u00e1z a epigenetick\u00fdmi lie\u010divami(15)<\/a>.<\/p>\n

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Vyu\u017eitie mas\u00edvne paraleln\u00e9ho sekvenovania v MSI diagnostike<\/h3>\n

Aktu\u00e1lne sa dost\u00e1va do popredia n\u00e1zor, \u017ee pou\u017eitie panelov\u00e9ho sekvenovania ako prvotn\u00e9ho skr\u00edningu MSI predstavuje v klinickej praxi cenovo efekt\u00edvny sp\u00f4sob diagnostiky Lynchovho syndr\u00f3mu a in\u00fdch n\u00e1dorov\u00fdch a polyp\u00f3znych syndr\u00f3mov(16)<\/a>, pri\u010dom sekvenovanie n\u00e1doru ako prvotn\u00fd krok pri skr\u00edningu Lynchovho syndr\u00f3mu m\u00f4\u017ee nahradi\u0165 s\u00fa\u010dasne pou\u017e\u00edvan\u00e9 pr\u00edstupy(17)<\/a>. Ve\u013ekou v\u00fdhodou NGS met\u00f3d oproti MSI- PCR je predov\u0161etk\u00fdm s\u00fabor analyzovan\u00fdch markerov, ktor\u00fd var\u00edruje a\u017e po nieko\u013eko tis\u00edc. Okrem vy\u0161\u0161ej citlivosti je to v niektor\u00fdch pr\u00edpadoch absencia p\u00e1rovej vzorky kontroln\u00e9ho nen\u00e1dorov\u00e9ho tkaniva, ktor\u00e1 je pre pr\u00edstupy MSI-PCR nevyhnutn\u00e1. D\u00f4kazy o adekv\u00e1tnosti mas\u00edvne paraleln\u00e9ho sekvenovania pri detekcii MSI poskytlo sekvenovanie \u0161tandardne pou\u017e\u00edvan\u00e9ho g\u00e9nov\u00e9ho panela Bethesda\/NCI. Z\u00edskan\u00e9 v\u00fdsledky korelovali s met\u00f3dou MSI-PCR anal\u00fdzy, \u010do demon\u0161truje, \u017ee pr\u00edstupy zalo\u017een\u00e9 na vysokoparalelnom sekvenovan\u00ed predstavuj\u00fa vhodn\u00fa skr\u00edningov\u00fa a diagnostick\u00fa met\u00f3dou na testovanie MSI(18)<\/a>. Detekcia MSI vych\u00e1dzaj\u00faca z rozli\u010dn\u00fdch sekvena\u010dn\u00fdch platforiem dosahuje vysok\u00fa \u0161pecificitu a senzitivitu, \u010do demon\u0161truje, \u017ee tento pr\u00edstup m\u00f4\u017ee v bl\u00edzkom \u010dase plnohodnotne nahradi\u0165 konven\u010dne pou\u017e\u00edvan\u00e9 skr\u00edningov\u00e9 met\u00f3dy(19)<\/a>. Vybran\u00e9 \u0161t\u00fadie zaoberaj\u00face sa detekciou MSI v n\u00e1doroch kolorekta pomocou mas\u00edvne paraleln\u00e9ho\u00a0sekvenovania zobrazuje tabu\u013eka 3<\/strong>. Napriek \u0161irok\u00e9mu spektru n\u00e1strojov na vyhodnocovanie MSI zo sekven\u010dn\u00fdch d\u00e1t vykazuj\u00facich v porovnan\u00ed s MSI-PCR konkordanciu, ktor\u00e1 var\u00ed- ruje od 92,3 % do 100 %(19-21)<\/a>, neboli doposia\u013e predstaven\u00e9 konsenzu\u00e1lne krit\u00e9ri\u00e1 na vyhodnocovanie MSI, \u010do do istej miery limituje ich zavedenie do rutinnej klinickej praxe.<\/p>\n

<\/h3>\n

Potenci\u00e1l cirkuluj\u00facej n\u00e1dorovej DNA v MSI diagnostike<\/h3>\n

Potenci\u00e1l cirkuluj\u00facej n\u00e1dorovej DNA (ctDNA, circulating <\/em>tumour DNA<\/em>) je pripisovan\u00fd vlastnostiam, ako je schopnos\u0165 sledova\u0165 progresiu n\u00e1dorov\u00e9ho ochorenia, mo\u017enos\u0165 predpoveda\u0165 recid\u00edvu n\u00e1doru a v neposlednom rade schopnos\u0165 odr\u00e1\u017ea\u0165 stav n\u00e1dorovej heterogenity(22)<\/a>. Z\u00e1rove\u0148 medzi MSI fenotypom v ctDNA a n\u00e1dorovom tkanive existuje vysok\u00e1 miera korel\u00e1cie. Ke\u010f\u017ee len mal\u00e1 \u010das\u0165 z fragmentov ctDNA v cirkul\u00e1cii poch\u00e1dza z n\u00e1dorov\u00fdch buniek, detekcia MSI zalo\u017een\u00e1 na b\u00e1ze tekutej biopsie si vy\u017eaduje ve\u013emi citliv\u00fd pr\u00edstup. Presnos\u0165 a citlivos\u0165 menej invaz\u00edvnych met\u00f3d zalo\u017een\u00fdch na anal\u00fdze vo\u013en\u00fdch cirkuluj\u00facich nukleov\u00fdch kysel\u00edn je ovplyvnen\u00e1 faktormi, medzi ktor\u00e9 patria napr\u00edklad technick\u00e9 a bioinformatick\u00e9 v\u00fdzvy pre efekt\u00edvne sekvenovanie, mapovanie, volanie variantov a korekciu ch\u00fdb v oblasti vysokorepetit\u00edvnych mikrosatelitn\u00fdch lokusov, n\u00edzka frakcia ctDNA v cirkul\u00e1cii, respekt\u00edve chyby vznikaj\u00face pri replik\u00e1cii gen\u00f3mu(23)<\/a>. Pr\u00edstupy na hodnotenie stavu MSI prostredn\u00edctvom anal\u00fdzy ctDNA dosahuj\u00fa konkordanciu na \u00farovni ~ 99 % pre status MSI medzi vzorkami tkaniva a ctDNA(12,24). Kritick\u00fdm parametrom esej\u00ed vych\u00e1dzaj\u00facich z anal\u00fdzy vo\u013en\u00fdch cirkuluj\u00facich nukleov\u00fdch kysel\u00edn je frakcia n\u00e1dorov\u00fdch buniek, preto\u017ee \u00fa\u010dinnos\u0165 detekcie MSI vo vzork\u00e1ch s vysokou kontamin\u00e1ciou zdrav\u00fdch buniek v\u00fdznamne kles\u00e1(24). V neposlednom rade je to heterogenita a dynamika n\u00e1doru, pri ktorej intera intratumorov\u00e1 variabilita s\u00fa k\u013e\u00fa\u010dov\u00fdm faktorom pri- spievaj\u00facim k nes\u00faladu medzi pacientmi\/kohortami. N\u00e1dorov\u00e9 bunky prech\u00e1dzaj\u00fa v odpovedi na stres sp\u00f4soben\u00fd prostred\u00edm a terapiou klon\u00e1lnou evol\u00faciou, ktor\u00e1 m\u00f4\u017ee meni\u0165 ich genetick\u00fa inform\u00e1ciu. Napriek tomu sa predpoklad\u00e1, \u017ee tekut\u00e1 biopsia m\u00e1 v porovnan\u00ed s tkanivom potenci\u00e1l nieko\u013ekon\u00e1sobne lep\u0161ieho z\u00e1chytu tumorovej heterogenity(23)<\/a>. Najnov\u0161ie valid\u00e1cie preukazuj\u00fa 100 % senzitivitu a \u0161pecificitu, a to aj v pr\u00edpade 0,05 % obsahu ctDNA(25). Napriek evidencii, \u017ee pr\u00edstupy zalo\u017een\u00e9 na anal\u00fdze ctDNA poskytuj\u00fa pri detekcii MSI pomocou vysokoparaleln\u00e9ho sekvenovania mikrosatelitn\u00fdch lokusov dostato\u010dn\u00fa citlivos\u0165, s\u00fa pre ich zavedenie do klinickej praxe potrebn\u00e9 \u010fal\u0161ie funk\u010dn\u00e9 valid\u00e1cie.<\/p>\n

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Z\u00e1ver<\/h3>\n

\u0160irok\u00e1 dostupnos\u0165 detekcie MSI pomocou vysokoparaleln\u00e9ho sekvenovania v klinickej praxi m\u00f4\u017ee v kone\u010dnom d\u00f4sledku eliminova\u0165 spektrum komplik\u00e1ci\u00ed, ktor\u00e9 s\u00fa spojen\u00e9 s aktu\u00e1lne zau\u017e\u00edvan\u00fdmi pr\u00edstupmi. Z\u00e1rove\u0148, neust\u00e1le inov\u00e1cie vo v\u00fdpo\u010dtov\u00fdch algoritmoch umo\u017e\u0148uj\u00fa rozsiahly skr\u00edning v desiatkach a\u017e stovk\u00e1ch vzoriek s\u00fa\u010dasne, so senzitivitou na \u00farovni konven\u010dne pou\u017e\u00edvan\u00fdch skr\u00edningov\u00fdch n\u00e1strojov. Anal\u00fdza telov\u00fdch tekut\u00edn okrem in\u00e9ho vedie ku kvalitnej\u0161iemu mana\u017ementu pacientovho ochorenia, a to pri monitorovan\u00ed odpovede tumoru na protin\u00e1dorov\u00fa terapiu aj pri sledovan\u00ed jeho pr\u00edpadnej recid\u00edvy.<\/p>\n

 <\/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 projekt <\/em>k\u00f3d ITMS: 313011V578, spolufinancovan\u00fd zo zdrojov Eur\u00f3pskeho fondu region\u00e1lneho rozvoja, T\u00e1to pr\u00e1ca bola podporen\u00e1 Agent\u00farou na podporu v\u00fdskumu a v\u00fdvoja <\/em>na z\u00e1klade Zmluvy \u010d. APVV-18-0319 a projektom <\/em>VEGA 1\/0305\/19<\/em><\/p>\n

 <\/p>\n

Konflikt z\u00e1ujmov<\/em><\/strong><\/p>\n

Autori vyhlasuj\u00fa, \u017ee nemaj\u00fa \u017eiadny konflikt z\u00e1ujmov.<\/em><\/p>\n

 <\/p>\n

LITERAT\u00daRA<\/strong><\/p>\n

    \n
  1. Tamura K, Kaneda M, Futagawa M, et al. Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome. Int J Clin On<\/em>col<\/em>. 2019;24(9):999-1011.<\/li>\n
  2. Nadir E, Margalit H, Gallily T, Ben-Sasson SA. Microsatellite spreading in the human genome: evolutionary mechanisms and structural implications. Proceedings of the National Academy of Sciences<\/em>. 1996;93(13):6470-6475.<\/li>\n
  3. Avvaru AK, Sharma D, Verma A, et MSDB: a comprehensive, annotated database of microsatellites. Nucleic Acids Res<\/em>. 2020;48(D1):D155-D159<\/li>\n
  4. Balzano E, Pelliccia F, Giunta S. Genome (in)stability at tandem reSeminars in Cell & Developmental Biology<\/em>. Published online 2020.<\/li>\n
  5. Sun JX, Helgason A, Masson G, et al. A direct characterization of human mutation based on Nat Genet<\/em>. 2012;44(10):1161- 1165.<\/li>\n
  6. Murat P, Guilbaud G, Sale DNA polymerase stalling at structured DNA constrains the expansion of short tandem repeats. Genome Biol<\/em>. 2020;21(1):209.<\/li>\n
  7. Copija A, Waniczek D, Witko\u015b A, et Clinical Significance and Prognostic Relevance of Microsatellite Instability in Sporadic Colorectal Cancer Patients. Int J Mol Sci<\/em>. 2017;18(1).<\/li>\n
  8. Hegde M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med<\/em>. 2014;16(1):101-116.<\/li>\n
  9. Arulananda S, Thapa B, Walkiewicz M, et Mismatch Repair Protein Defects and Microsatellite Instability in Malignant Pleural Mesothelioma. J Thorac Oncol<\/em>. 2018;13(10):1588-1594.<\/li>\n
  10. McCarthy AJ, Capo\u2010Chichi J, Spence T, et Heterogenous loss of mismatch repair (MMR) protein expression: a challenge for immunohistochemical interpretation and microsatellite instability (MSI) evaluation. The Journal of Pathology: Clinical Research<\/em>. 2019;5(2):115-129.<\/li>\n
  11. Shia J. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: part The utility of immunohistochemistry. J Mol Diagn<\/em>. 2008;10(4):293-300.<\/li>\n
  12. Zhang L. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpoly- posis colorectal cancer syndrome. Part II. The utility of microsatellite instability J Mol Diagn<\/em>. 2008;10(4):301-307.<\/li>\n
  13. Cohen R, Hain E, Buhard O, et Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status. JAMA Oncol<\/em>. 2019;5(4):551-555.<\/li>\n
  14. Luchini C, Bibeau F, Ligtenberg MJL, et ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1\/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Annals of Oncology<\/em>. 2019;30(8):1232- 1243.<\/li>\n
  15. Galluzzi L, Buqu\u00e9 A, Kepp O, et Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell<\/em>. 2015;28(6):690-714.<\/li>\n
  16. Gallego CJ, Shirts BH, Bennette CS, et Next-generation sequencing panels for the diagnosis of colorectal cancer and polyposis syndromes: a cost-effectiveness analysis. J Clin Oncol<\/em>. 2015;33(18):2084.<\/li>\n
  17. Hampel H, Pearlman R, Beightol M, et Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer. JAMA Oncol<\/em>. 2018;4(6):806-813.<\/li>\n
  18. Gan C, Love C, Beshay V, et Applicability of next generation sequencing technology in microsatellite instability testing. Genes <\/em>. 2015;6(1):46- 59<\/li>\n
  19. Zhu L, Huang Y, Fang X, et A Novel and Reliable Method to Detect Microsatellite Instability in Colorectal Cancer by Next-Generation Sequencing. J Mol Diagn<\/em>. 2018;20(2):225-231.<\/li>\n
  20. Niu B, Ye K, Zhang Q, et MSIsensor: microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics<\/em>. 2014;30(7):1015-1016.<\/li>\n
  21. Kautto EA, Bonneville R, Miya J, et Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS. Onco- <\/em>target<\/em>. 2017;8(5):7452-7463.<\/li>\n
  22. Myint NNM, Verma AM, Fernandez-Garcia D, et Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity. Cell Death & Disease<\/em>. 2018;9(9).<\/li>\n
  23. Wang L, Ajani Ushering in Liquid Biopsy for the Microsatellite Status: Advantages and Caveats. Clinical Cancer Research<\/em>. 2019;25(23):6887- 6889.<\/li>\n
  24. Willis J, Lefterova MI, Artyomenko A, et al. Validation of Microsatellite Instability Detection Using a Comprehensive Plasma-Based Genotyping Clinical Cancer Research<\/em>. 2019;25(23):7035-7045.<\/li>\n
  25. Han X, Zhang S, Zhou DC, et al. MSIsensor-ct: microsatellite instability detection using cfDNA sequencing data. Brief Bioinform<\/em>. Published online 18 January<\/li>\n
  26. Lee Y, Lee JA, Park HE, et Targeted next-generation sequenc- ing-based detection of microsatellite instability in colorectal carcinomas. PLoS One<\/em>. 2021;16(2):e0246356.<\/li>\n
  27. Kim JE, Chun S-M, Hong YS, et Mutation Burden and I Index for Detection of Microsatellite Instability in Colorectal Cancer by Targeted Next-Generation Sequencing. J Mol Diagn<\/em>. 2019;21(2):241-250.<\/li>\n
  28. Nowak JA, Yurgelun MB, Bruce JL, et Detection of Mismatch Repair Deficiency and Microsatellite Instability in Colorectal Adenocarcinoma by Targeted Next-Generation Sequencing. J Mol Diagn<\/em>. 2017;19(1):84-91.<\/li>\n
  29. Hempelmann JA, Scroggins SM, Pritchard CC, Salipante MSIplus for Integrated Colorectal Cancer Molecular Testing by Next-Generation Sequencing. J Mol Diagn<\/em>. 2015;17(6):705-714.<\/li>\n<\/ol>\n

     <\/p>\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   Lynchov syndr\u00f3m je autozom\u00e1lne dominantn\u00e9 dedi\u010dn\u00e9 ochorenie charakterizovan\u00e9 defektmi v syst\u00e9me opravy chybne sp\u00e1rovan\u00fdch b\u00e1z \u2013 MMR syst\u00e9me (mismatch repair system). Ide o postreplikat\u00edvny opravn\u00fd syst\u00e9m zais\u0165uj\u00faci integritu gen\u00f3mu prostredn\u00edctvom repar\u00e1cie chybne inkorporovan\u00fdch nukleotidov,<\/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":[1068,1183,1768],"class_list":["post-2279","post","type-post","status-publish","format-standard","hentry","category-genetics","tag-lynch-syndrome","tag-massively-parallel-sequencing","tag-microsatellite-instability","typ_clanku-review-article"],"acf":{"abstrakt":"

    Microsatellite instability (MSI) is a state of genomic alteration occurring in the region of microsatellites, usually formed by 1 – 6 nucleotide repeats, which accumulate indels of several base pair sizes. It is well known that the determination of the degree of MSI is a critical parameter for lifelong screening of patients with Lynch syndrome. Currently available diagnostic approaches in clinical practice, which are used to detect MSI, have certain limitations. Modern next-generation sequencing technologies, combined with liquid biopsy analysis, have great potential to overcome these limitations. Several studies have shown that massively parallel sequencing technology, coupled with appropriate bioinformatics tools, can provide a more accurate, cost-effective, and affordable approach to detecting and screening MSI in Lynch syndrome-associated tumours.<\/p>\n

    Keywords:<\/strong> Lynch syndrome, microsatellite instability, massively parallel sequencing<\/p>\n","casopis":[{"ID":2233,"post_author":"7","post_date":"2021-09-19 22:32:27","post_date_gmt":"2021-09-19 20:32:27","post_content":"We\u2019re bringing you this year\u2019s 1st<\/sup> issue of newslab, the scientific journal<\/strong>\r\n\r\n \r\n

      \r\n \t
    • Genomic variability of virus Sars-CoV-2<\/li>\r\n \t
    • Contribution of immunohistochemistry to histomorphological diagnostics of COVID-19 pneumonia<\/li>\r\n \t
    • Detection of microsatellite instability in Lynch syndrome-associated tumours<\/li>\r\n \t
    • Comparison of platelet glycoprotein analysis in the wholeh blood and plasma rich in platelets<\/li>\r\n \t
    • Tspan1 expression in prostatic adenocarcinoma<\/li>\r\n<\/ul>","post_title":"newslab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-8","to_ping":"","pinged":"","post_modified":"2021-09-19 22:36:56","post_modified_gmt":"2021-09-19 20:36:56","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.newslab.sk\/casopis\/newslab-8\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"27 - 31","upload_clanok":{"ID":2277,"id":2277,"title":"NEWSLAB 1-2021_Styk","filename":"NEWSLAB-1-2021_Styk.pdf","filesize":463012,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2021\/09\/NEWSLAB-1-2021_Styk.pdf","link":"https:\/\/www.newslab.sk\/en\/detection-of-microsatellite-instability-in-lynch-syndrome-associated-tumours\/newslab-1-2021_styk-2\/","alt":"","author":"7","description":"","caption":"","name":"newslab-1-2021_styk-2","status":"inherit","uploaded_to":2279,"date":"2021-09-20 07:35:45","modified":"2021-09-20 07:35:45","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\/2279","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=2279"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/2279\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=2279"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=2279"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=2279"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}