{"id":1029,"date":"2017-04-07T14:02:19","date_gmt":"2017-04-07T12:02:19","guid":{"rendered":"http:\/\/www.newslab.sk\/2017\/04\/07\/diferencialna-molekulova-diagnostika-mnohopocetneho-myelomu-a-waldenstromovej-makroglobulinemie\/"},"modified":"2017-10-03T09:17:24","modified_gmt":"2017-10-03T07:17:24","slug":"differential-molecular-diagnosis-of-multiple-myeloma-and-waldenstrom-macroglobulinemia","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/differential-molecular-diagnosis-of-multiple-myeloma-and-waldenstrom-macroglobulinemia\/","title":{"rendered":"Differential molecular diagnosis of multiple myeloma and Waldenstr\u00f6m macroglobulinemia"},"content":{"rendered":"<pre><strong><span style=\"color: #ff0000;\">*V\u0161etky tabu\u013eky, grafy a obr\u00e1zky, ktor\u00e9 s\u00fa s\u00fa\u010das\u0165ou \u010dl\u00e1nku, n\u00e1jdete v prilo\u017eenom \r\nPDF s\u00fabore na konci \u0161t\u00fadie.<\/span>\r\n\r\n<\/strong><\/pre>\n<p><strong>\u00davod<\/strong><\/p>\n<p>Mnohopo\u010det\u00fd myel\u00f3m \u00a0(MM) patr\u00ed\u00a0 medzi hematoonkologick\u00e9 ochorenia plazmatick\u00fdch B-buniek. Vo v\u00e4\u010d\u0161ine pr\u00edpadov prevl\u00e1da v\u00fdskyt n\u00e1dorov\u00fdch buniek typu zrel\u00fdch plazmocytov s n\u00edzkou prolifera\u010dnou aktivitou. Lokaliz\u00e1cia uveden\u00fdch patologick\u00fdch foriem je striktne viazan\u00e1 na mikroprostredie kostnej drene, kde prebieha ich prolifer\u00e1cia a diferenci\u00e1cia(1). MM sa rad\u00ed do skupiny \u00a0monoklon\u00e1lnych gamapati\u00ed, preto\u017ee jedn\u00fdm z jeho z\u00e1kladn\u00fdch znakov \u00a0je produkcia monoklon\u00e1lnych protil\u00e1tok. Za fyziologick\u00fdch podmienok sa v s\u00e9re \u00a0zdrav\u00e9ho \u00a0jedinca vyskytuj\u00fa \u00a0polyklon\u00e1lne imunoglobul\u00edny, \u00a0ktor\u00e9 s\u00fa \u00a0schopn\u00e9 podlieha\u0165 rekombin\u00e1ci\u00e1m a vytv\u00e1ra\u0165 tak \u0161irok\u00e9 spektrum v\u00e4zbov\u00fdch miest pre r\u00f4zne antig\u00e9ny. Pri monoklon\u00e1lnych gamapati\u00e1ch vr\u00e1tane MM doch\u00e1dza v organizme k produkcii \u00a0jedn\u00e9ho antig\u00e9nne i \u0161trukt\u00farne konzistentn\u00e9ho antig\u00e9nu, pr\u00edpadne jeho fragmentu, \u010d\u00edm \u00a0je zna\u010dne zn\u00ed\u017een\u00e1 efektivita \u00a0imunitn\u00e9ho syst\u00e9mu. Monoklon\u00e1lne imunoglobul\u00edny postupne infiltruj\u00fa kostn\u00fa dre\u0148, kde nahr\u00e1dzaj\u00fa funk\u010dn\u00e9 plazmocyty(2).<\/p>\n<p><strong>P<\/strong><strong>atogen\u00e9za <\/strong><strong>MM<\/strong><\/p>\n<p>MM prebieha ako \u00a0viac\u00farov\u0148ov\u00fd proces, ktor\u00fd sa za\u010d\u00edna ako premal\u00edgne \u0161t\u00e1dium, resp. \u00a0monoklon\u00e1lna gamapatia nejasn\u00e9ho v\u00fdznamu \u00a0(MGUS) s variabilnou d\u013a\u017ekou \u00a0trvania. Od plne rozvinut\u00e9ho patologick\u00e9ho stavu \u00a0sa l\u00ed\u0161i ni\u017e\u0161ou hodnotou\u00a0 paraprote\u00ednu M, kostn\u00e1 dre\u0148 \u00a0obsahuje menej \u00a0ako \u00a010 % mononukle\u00e1rnych buniek \u00a0a nie s\u00fa \u00a0pr\u00edtomn\u00e9 \u010fal\u0161ie sympt\u00f3my a po\u0161kodenia org\u00e1nov(3). \u201eSmoldering\u201c myel\u00f3m (SMM) je heterog\u00e9nna prechodn\u00e1 forma \u00a0medzi \u00a0MGUS a plne rozvinut\u00fdm ochoren\u00edm. Odl\u00ed\u0161enie \u00a0SMM a MGUS je mo\u017en\u00e9 len na z\u00e1klade hodnotenia laborat\u00f3rnych v\u00fdsledkov. Hlavn\u00fdm diferencia\u010dn\u00fdm faktorom je pr\u00edtomnos\u0165 vy\u0161\u0161ej hladiny paraprote\u00ednu (nad 30 g\/l) a plazmatick\u00fdch buniek (nad 10 %) v kostnej dreni, ale\u00a0 z\u00e1rove\u0148 nesm\u00fa by\u0165 u pacienta pr\u00edtomn\u00e9 \u017eiadne \u010fal\u0161ie pr\u00edznaky \u00a0ako hyperkalci\u00e9mia, po\u0161kodenie obli\u010diek alebo an\u00e9mia(4). D\u00f4sledkom progresie n\u00e1dorovej masy je tie\u017e potla\u010denie \u00a0hostite\u013eskej imunity, preto \u00a0po\u010das transform\u00e1cie SMM na\u00a0 myel\u00f3m \u00a0doch\u00e1dza k vzniku pr\u00eddavn\u00fdch deficienci\u00ed celul\u00e1rnych \u00a0aj humor\u00e1lnych zlo\u017eiek imunity. \u00a0Nast\u00e1va postupn\u00e9 zhor\u0161enie org\u00e1nov\u00fdch funkci\u00ed s mo\u017enos\u0165ou roz\u0161\u00edrenia tumorov\u00fdch buniek \u00a0do extramedul\u00e1rnych oblast\u00ed, \u00a0naj\u010dastej\u0161ie do pe\u010dene a sleziny(5).<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Molekulov\u00e1 cytogenetika <\/strong><strong>MM<\/strong><\/p>\n<p>Ako prim\u00e1rne mut\u00e1cie sa pri MM ozna\u010duj\u00fa translok\u00e1cie zah\u0155\u0148aj\u00face lokus \u00a0pre \u0165a\u017ek\u00fd (<em>IgH<\/em>) imunoglobul\u00ednov\u00fd re\u0165azec alebo \u00a0jeden z lokusov pre \u013eahk\u00fd Ig re\u0165azec (IgL \u2013 kappa\/lambda).<\/p>\n<p>Uveden\u00e9 mut\u00e1cie s\u00fa pr\u00edtomn\u00e9 u viac ako polovice pacientov. Vznikaj\u00fa ako d\u00f4sledok nespr\u00e1vnej \u201ecrosswitch\u201c rekombin\u00e1cie a somatickej hypermut\u00e1cie protil\u00e1tok. <em>IgH <\/em>translok\u00e1cie zah\u0155\u0148aj\u00fa pri MM tri cie\u013eov\u00e9 skupiny onkog\u00e9nov, uveden\u00e9 v <strong><em>tabu\u013eke 1<\/em><\/strong>. Zvy\u010dajne ide o vyv\u00e1\u017een\u00e9 translok\u00e1cie, po\u010das ktor\u00fdch sa onkog\u00e9ny dostan\u00fa pod kontrolu siln\u00e9ho\u00a0 Ig intr\u00f3nov\u00e9ho enhaceru Emu a\/alebo <em>IgH <\/em>alfa(6). \u00a0V r\u00e1mci sekund\u00e1rnych aber\u00e1ci\u00ed doch\u00e1dza pri MM naj\u010dastej\u0161ie k mut\u00e1ci\u00e1m zah\u0155\u0148aj\u00facim chromoz\u00f3my 1, 13, 17 a v\u00fdnimkou nie s\u00fa ani translok\u00e1cie chromoz\u00f3mov 4, 11 a 14. Tumory plazmatick\u00fdch buniek s t(11;14)(q13;q32) s\u00fa \u00a0pri MM a MGUS asociovan\u00e9 s nadprodukciou cykl\u00ednu D1 (CCND1), ale paradoxne s\u00fa pri zaveden\u00ed vhodnej lie\u010dby spojen\u00e9 s dlh\u0161\u00edm pre\u017e\u00edvan\u00edm pacientov(7).<\/p>\n<p>&nbsp;<\/p>\n<p><strong>W<\/strong><strong>aldenstr\u00f6mova makroglobulin\u00e9mia \u00a0a g\u00e9n <\/strong><strong><em>M<\/em><\/strong><strong><em>YD88<\/em><\/strong><\/p>\n<p>Waldenstr\u00f6mova makroglobulin\u00e9mia (WM) je lymfoproliferat\u00edvne \u00a0ochorenie B-lymfocytov a z\u00e1rove\u0148 jeden z podtypov non-Hodgkinov\u00fdch lymf\u00f3mov. Prim\u00e1rnou \u010drtou je infiltr\u00e1cia kostnej drene \u00a0patologick\u00fdmi plazmocyt\u00e1rnymi bunkami a pr\u00edtomnos\u0165 Ig monoklon\u00e1lnej gamapatie. K naj\u010dastej\u0161\u00edm sprievodn\u00fdm javom patr\u00ed \u00a0an\u00e9mia, hypervisk\u00f3zny syndr\u00f3m, hepatosplenomeg\u00e1lia \u010di lymfadenopatie. Histologick\u00e1 transform\u00e1cia buniek \u00a0b\u00fdva pr\u00ed\u010dinou \u00a0progresie ochorenia do \u0161t\u00e1dia dif\u00faznej B-bunkovej leuk\u00e9mie (DLBCL), ke\u010f doch\u00e1dza ku komplexn\u00e9mu zhor\u0161eniu sympt\u00f3mov s extramedul\u00e1rnym postihnut\u00edm(8). Kandid\u00e1tnym g\u00e9nom pri WM je <em>MYD88 <\/em>(myeloid differentiation primary response 88) lokalizovan\u00fd \u00a0na chromoz\u00f3me 3p22. K\u00f3duje 31 \u2013 33 kDa adaptorov\u00fd prote\u00edn, ktor\u00fd obsahuje N-termin\u00e1lnu \u201edeath\u201c dom\u00e9nu (DD) a C-termin\u00e1lnu TIR dom\u00e9nu (Toll\/interleukin-1 receptor). Funkciou \u00a0prote\u00ednu je ukotvenie sign\u00e1lnych molek\u00fal na TIR dom\u00e9nu a na receptory pre interfer\u00f3n-\u03b3 (IFN-\u03b3) na zabezpe\u010denie spr\u00e1vneho fungovania vroden\u00fdch imunitn\u00fdch reakci\u00ed. Deregul\u00e1cia g\u00e9nu <em>MYD88 <\/em>m\u00e1 v preva\u017enej v\u00e4\u010d\u0161ine pr\u00edpadov negat\u00edvny d\u00f4sledok na sign\u00e1lne dr\u00e1hy NF-\u03baB, PI3K\/Akt\/mTOR \u010di JAK\/STAT(9).<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Somatick\u00e1 \u00a0mut\u00e1cia L265P<\/strong><\/p>\n<p>Somatick\u00fd variant (T\u2192C) v chromoz\u00f3movej oblasti 3p22.2 je jednozna\u010dn\u00fdm diagnostick\u00fdm markerom WM. Mut\u00e1cia zapr\u00ed\u010di\u0148uje aminokyselinov\u00fa z\u00e1menu leuc\u00ednu za prol\u00edn (L265P) v g\u00e9ne \u00a0<em>MYD88<\/em>, \u010doho \u00a0n\u00e1sledkom je abnorm\u00e1lne vysok\u00e1 \u00a0aktivita uveden\u00fdch sign\u00e1lnych dr\u00e1h. \u00a0V\u00fdsledkom komplexn\u00e9ho patologick\u00e9ho procesu je tak mal\u00edgna prolifer\u00e1cia a supresia apopt\u00f3zy B-lymfocytov(10,11).<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Diferenci\u00e1lna diagnostika monoklon\u00e1lnych <\/strong><strong>gamapati\u00ed <\/strong><\/p>\n<p>Potvrdenie diagn\u00f3zy monoklon\u00e1lnych gamapati\u00ed zah\u0155\u0148a s\u00e9riu biochemick\u00fdch vy\u0161etren\u00ed, \u00a0predov\u0161etk\u00fdm elektrofor\u00e9zu s\u00e9rov\u00fdch bielkov\u00edn (SPEP) a elektrofor\u00e9zu bielkov\u00edn v mo\u010di (UPEP). Separ\u00e1cia na klasickej agar\u00f3ze v kombin\u00e1cii s imunofix\u00e1ciou sa vyu\u017e\u00edva ako \u00a0skr\u00edningov\u00e1 met\u00f3da na detekciu pr\u00edtomnosti M-prote\u00ednu \u00a0a jeho \u00a0\u0165a\u017ek\u00fdch \u00a0Ig re\u0165azcov \u00a0a determin\u00e1ciu \u013eahk\u00fdch \u00a0Ig \u00a0re\u0165azcov. Preto\u017ee uveden\u00e9 met\u00f3dy s\u00fa relat\u00edvne \u00a0neinvaz\u00edvne, je vhodn\u00e9 \u00a0vykona\u0165 ich u v\u0161etk\u00fdch pacientov. \u00a0Pri UPEP je nevyhnutn\u00fd 24-hodinov\u00fd odber \u00a0mo\u010du, preto\u017ee mno\u017estvo M-prote\u00ednu \u00a0v \u0148om \u00a0je nepriamym meradlom rozsahu tumorovej masy(12). Met\u00f3dy fluorescen\u010dnej <em>i<\/em><em>n <\/em><em>situ <\/em>hybridiz\u00e1cie (FISH) sa rutinne vyu\u017e\u00edvaj\u00fa na anal\u00fdzu chromoz\u00f3mov\u00fdch aber\u00e1ci\u00ed, naj\u010dastej\u0161ie \u00a0t(11,14), ktor\u00e1 \u00a0priamo s\u00favis\u00ed \u00a0so zv\u00fd\u0161enou expresiou CCND1 a je typick\u00e1 \u00a0pr\u00e1ve \u00a0pre MM. V\u00fdznamn\u00fdm \u00a0markerom monoklon\u00e1lnych gamapati\u00ed s\u00fa tie\u017e prestavby IgH lokusu a \u010dast\u00e9 s\u00fa aj del\u00e9cie 17p13 \u00a0(<em>TP53<\/em>) a 13q14 (<em>RB1<\/em>). Na molekulovej \u00farovni mo\u017eno potvrdi\u0165 pr\u00edtomnos\u0165 najfrekventovanej\u0161\u00edch genomick\u00fdch del\u00e9ci\u00ed \u00a0a\u00a0 duplik\u00e1ci\u00ed met\u00f3dou MLPA (multiple \u00a0ligation-dependent probe amplification). Vyu\u017eit\u00edm kvantitat\u00edvnej real-time \u00a0PCR mo\u017eno sledova\u0165 \u00a0hladinu expresie CCND1, ktor\u00e1 u pacientov koreluje s mierou \u00a0lie\u010debnej odpovede.<\/p>\n<p>Probl\u00e9mom v rutinnej praxi je skuto\u010dnos\u0165, \u017ee v\u00fdsledky uveden\u00fdch laborat\u00f3rnych testov s\u00fa pri WM a MM do\u00a0 zna\u010dnej miery rovnak\u00e9, \u00a0\u010do m\u00f4\u017ee \u00a0vies\u0165 k nepresnej diagnostike dan\u00e9ho ochorenia, a t\u00fdm aj k podaniu ne\u0161pecifickej lie\u010dby. U pacientov \u00a0s MM sa vyu\u017e\u00edva kombin\u00e1cia cytostat\u00edk a kortikosteroidov, pr\u00edpadne imunomodula\u010dn\u00e9 l\u00e1tky. Medzi najnov\u0161ie lie\u010div\u00e1 z oblasti cielenej \u00a0terapie MM patr\u00ed talidomid, \u00a0inhib\u00edtory VEGF (vascular endothelial growth factor) alebo \u00a0proteaz\u00f3mov\u00e9 inhib\u00edtory(13). U pacientov s WM je pomerne \u010dast\u00fd v\u00fdskyt neuropati\u00ed a hemolytickej an\u00e9mie. V danom pr\u00edpade je prvou vo\u013ebou rituximab, ktor\u00fd zabezpe\u010duje elimin\u00e1ciu \u00a0mal\u00edgnych B-lymfocytov prezentuj\u00facich povrchov\u00fd antig\u00e9n CD20. Pri progresii ochorenia sa vyu\u017e\u00edva trojkombin\u00e1cia DRC (dexametaz\u00f3n, rituximab, cyklofosfamid)(14). Pre \u00a0aplik\u00e1ciu vhodn\u00e9ho \u00a0lie\u010debn\u00e9ho algoritmu je teda \u00a0nevyhnutn\u00e1 spo\u013eahliv\u00e1 diferenci\u00e1lna diagnostika, ktorou mo\u017eno odl\u00ed\u0161i\u0165 uveden\u00e9 monoklon\u00e1lne gamapatie na molekulovej \u00farovni.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Materi\u00e1l a metodika<\/strong><\/p>\n<p><strong><em>Vzorky<\/em><\/strong><\/p>\n<p>Do s\u00faboru pacientov s podozren\u00edm na\u00a0 Waldenstr\u00f6movu makroglobulin\u00e9miu boli zahrnut\u00e9 vzorky kostnej drene spracovan\u00e9 na oddelen\u00ed lek\u00e1rskej genetiky \u00a0v Medirexe, a. s., v \u010dasovom rozmedz\u00ed od okt\u00f3bra 2015 do marca 2016. S\u00fabor bol zostaven\u00fd z 29 vzoriek. DNA na anal\u00fdzy bola izolovan\u00e1 kitom QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany) pod\u013ea prilo\u017een\u00e9ho protokolu. Koncentr\u00e1cia a kvalita vzoriek bola meran\u00e1 na Implen \u00a0nanofotometri (Implen GmbH, Munchen, Germany). Ako negat\u00edvne kontroly boli pou\u017eit\u00e9 vzorky od pacientov \u00a0bez onkologick\u00fdch diagn\u00f3z.<\/p>\n<p>&nbsp;<\/p>\n<p><strong><em>Alelovo \u0161pecifick\u00e1 PCR (AS-PCR)<\/em><\/strong><\/p>\n<p>Pri optimaliz\u00e1cii \u00a0vhodnej \u00a0AS-PCR boli \u00a0pou\u017eit\u00e9 \u00a0komer\u010dne\u00a0 dostupn\u00e9 primery \u00a0od firmy Sigma-Aldrich \u00a0pre wild-type a mutovan\u00fd typ alel. Reak\u010dn\u00e9 mixy boli pripraven\u00e9 s viacer\u00fdmi druhmi \u00a0polymer\u00e1z vr\u00e1tane Pfu Turbo Cx Hotstart, AmpliTaq Gold a Phu. Ide\u00e1lny priebeh \u00a0reakcie bol dosiahnut\u00fd iba v pr\u00edpade poslednej Phu polymer\u00e1zy. Genomick\u00e1 DNA bola narieden\u00e1 na 10 ng a teplotn\u00fd \u00a0program bol nastaven\u00fd pod\u013ea \u010dl\u00e1nku Varettoni \u00a0et al., 2013(12). Ve\u013ekos\u0165 z\u00edskan\u00fdch PCR produktov bola pribli\u017ene 300 bp.<\/p>\n<p>&nbsp;<\/p>\n<p><strong><em>Sekvenovanie <\/em><\/strong><strong><em>a <\/em><\/strong><strong><em>MLPA <\/em><\/strong><strong><em>anal\u00fdza<\/em><\/strong><\/p>\n<p>Z\u00edskan\u00e9 PCR produkty \u00a0boli enzymaticky purifikovan\u00e9 pomocou Exo Sap (Applied Biosystems, Foster City, USA), ktor\u00fd zo zmesi odstr\u00e1ni nezainkorporovan\u00e9 primery a dNTP. Na pr\u00edpravu sekvena\u010dnej reakcie bol pou\u017eit\u00fd BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, USA) a na fin\u00e1lnu purifik\u00e1ciu \u00a0DyeEx 2.0 Spin Kit (Qiagen, Hilden, Germany) \u00a0so \u017eivicov\u00fdmi kol\u00f3nkami. Vzorky sme sekvenovali na genetickom analyz\u00e1tore ABI 3500 (Applied Biosystems, Foster City, \u00a0USA) a vyhodnotili pomocou softv\u00e9ru SeqScape. V\u00fdsledky \u00a0sme overili vlo\u017een\u00edm sekvenci\u00ed \u00a0do BLAST-u a tie\u017e pomocou MLPA anal\u00fdzy (MRC Holland, Amsterdam, The Netherlands). Pou\u017eit\u00fd \u00a0probemix SALA MLPA P038 \u00a0B1 obsahuje 51 \u0161pecifick\u00fdch pr\u00f3b pre B-bunkov\u00e9 aber\u00e1cie vr\u00e1tane somatickej mut\u00e1cie L265P v g\u00e9ne <em>MYD88<\/em>.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>V<\/strong><strong>\u00fdsledky<\/strong><\/p>\n<p>Kombin\u00e1ciou komer\u010dne dostupn\u00fdch primerov, Phu polymer\u00e1zy a protokolu pod\u013ea Varettoni \u00a0et al., 2013 sme zostavili \u00a0vhodn\u00fa \u00a0AS-PCR, ktorej \u00a0produkty \u00a0mo\u017eno pou\u017ei\u0165 na \u010fal\u0161ie \u00a0sekvenovanie \u00a0a \u00a0detekciu mut\u00e1cie v g\u00e9ne\u00a0 \u00a0<em>MYD88<\/em>. V na\u0161om s\u00fabore analyzovan\u00fdch pacientov sme pozitivitu v\u00fdsledkov \u00a0hodnotili \u00a0na z\u00e1klade z\u00e1meny tym\u00ednu \u00a0za cytoz\u00edn na\u00a0978 \u00a0nukleotide <strong><em>(obr\u00e1zok \u00a01)<\/em><\/strong>. Z\u00edskan\u00e9 v\u00fdsledky sme potvrdili aj MLPA anal\u00fdzou <strong><em>(obr\u00e1zok 2)<\/em><\/strong>. Uveden\u00fdmi met\u00f3dami sa n\u00e1m podarilo \u00a0zostavi\u0165 \u00a0diagnostick\u00fd algoritmus vhodn\u00fd na detekciu pacientov s WM a odl\u00ed\u0161i\u0165 ich tak od ostatn\u00fdch pr\u00edpadov MM \u010di in\u00fdch monoklon\u00e1lnych gamapati\u00ed. Po\u010das anal\u00fdzy pacientov \u00a0sme detegovali aj \u010fal\u0161\u00edch \u00a011 polymorfizmov v g\u00e9ne <em>MYD88<\/em>, ktor\u00e9 v\u0161ak nemali \u017eiadny fenotypov\u00fd prejav.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Diskusia<\/strong><\/p>\n<p>Waldenstr\u00f6mova makroglobulin\u00e9mia rovnako \u00a0ako myel\u00f3m patr\u00ed medzi lymfoproliferat\u00edvne ochorenia B-buniek s v\u00fdskytom monoklon\u00e1lnych protil\u00e1tok. Ke\u010f\u017ee je pomerne \u0165a\u017ek\u00e9 odl\u00ed\u0161i\u0165 MM od WM na z\u00e1klade klinick\u00e9ho obrazu a v\u00fdsledkov laborat\u00f3rnych testov, bolo na\u0161\u00edm cie\u013eom zavies\u0165 \u00a0do rutinnej diagnostiky molekulov\u00fa met\u00f3du, ktor\u00e1 by spo\u013eahlivo identifikovala konkr\u00e9tny \u00a0typ ochorenia. Publik\u00e1cie z posledn\u00fdch rokov uv\u00e1dzaj\u00fa somatick\u00fa mut\u00e1ciu L265P v g\u00e9ne <em>MYD88 <\/em>ako diagnostick\u00fd marker \u00a0jedine\u010dn\u00fd pre WM, preto\u017ee pri MM sa nenach\u00e1dza. WM je relat\u00edvne zriedkav\u00e9 ochorenie v r\u00e1mci hematoonkologick\u00fdch malign\u00edt. Glob\u00e1lne je zaznamenan\u00fdch pribli\u017ene 5 pacientov na 1 mili\u00f3n pr\u00edpadov. Po\u010das diagnostiky nov\u00fdch pacientov sme zaznamenali \u010dast\u00fd v\u00fdskyt bodov\u00fdch\u00a0polymorfizmov, najm\u00e4 \u00a02856 A &gt; R. Vo v\u00e4\u010d\u0161ine pr\u00edpadov \u00a0v\u0161ak i\u0161lo o silent \u00a0mut\u00e1cie a v \u017eiadnom z pr\u00edpadov \u00a0sme nedetegovali fenotypov\u00fd prejav.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Z\u00e1ver<\/strong><\/p>\n<p>Molekulov\u00e9 \u00a0met\u00f3dy maj\u00fa \u00a0v laborat\u00f3rnej praxi nezastupite\u013en\u00fd v\u00fdznam, preto\u017ee prispievaj\u00fa k presnej a relat\u00edvne \u00a0r\u00fdchlej diagnostike mnoh\u00fdch ochoren\u00ed. Pomocou vhodne \u00a0zvolen\u00e9ho algoritmu je mo\u017en\u00fd spo\u013eahliv\u00fd mana\u017ement pacientov \u010di samotn\u00e9 sledovanie lie\u010debnej odpovede.<\/p>\n<p>&nbsp;<\/p>\n<p><strong><em>P<\/em><\/strong><strong><em>o\u010fako<\/em><\/strong><strong><em>v<\/em><\/strong><strong><em>anie<\/em><\/strong><\/p>\n<pre><em>Tento \u010dl\u00e1nok vznikol v\u010faka podpore projektu VEGA 1\/0906\/<\/em>\r\n<\/pre>\n<p>&nbsp;<\/p>\n<p><strong>Literat\u00fara<\/strong><br \/>\n1. Boyle EM, Davies FE, Leleu X, et al. Understanding the multiple biological aspect leading to myeloma. Haematologica 2014; 99(4): 605- 612.<br \/>\n2. Matsui W, Wang Q, Barber JP, et al. Clonogenic Multiple Myeloma Progenitors, Stem Cell Properties, and Drug Resistance. Cancer Res 2008; 68(1): 190-197.<br \/>\n3. Chesi M, Bergsagel PL. Molecular pathogenesis of multiple myeloma: basic and clinical updates. Int J Hematol 2013; 97: 313-323.<br \/>\n4. Korde N, Kristinsson SY, Landgren O. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood 2011; 117(21): 5573-5581.<br \/>\n5. Kristinsson SY, Goldin LR, Bj\u00f6rkholm M, et al. Genetic and immune-related factors in the pathogenesis of lymphoproliferative and plasma cell malignancies. Haematologica, 2009 94: 1581-1589.<br \/>\n6. Chesi M, Bergsagel PL. Many Multiple Myelomas: Making More of the Molecular Mayhem. Hematology 2011; 344-353.<br \/>\n7. Raab MS, Podar K, Breitkreutz I, et al. Multiple myeloma. Lancet 2009; 374: 324-329.<br \/>\n8. Braggio E, Philipsborn C, Novak A, et al. Molecular Pathogenesis of Waldenstr\u00f6m\u2019s Macroglobulinemia. Haematologica 2012; 97(9): 1281-1290.<br \/>\n9. Olson A, Lee MS, Kissner TL, et al. Discovery of Small Molecule Inhibitors of MyD88-Dependent Signaling Pathways Using a Computational Screen. 2015; Online Available: www.nature.com\/scientificreports.<br \/>\n10. Treon SP, Hunter ZR. A New Era for Waldenstrom Macroglobulinemia: MYD88 L265P. Blood 2013; 121(22): 4434-4436.<br \/>\n11. Hamadeh F, MacNamara SP, Aguilera NS, et al. MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma. Modern Pathology 2015; 28: 564-574.<br \/>\n12. Molle P. Current Trends in the Diagnosis, Therapy and Monitoring of the Monoclonal Gammopathies. Clin Biochem Rev 2009; 30: 93-103.<br \/>\n13. \u0160pi\u010dka I, Bart\u00fankov\u00e1 J, Campr V, et al. Mnohopo\u010detn\u00fd myel\u00f3m a dal\u0161\u00ed monoklon\u00e1ln\u00ed gamapatie. Praha: Gal\u00e9n 2005. 125p.<br \/>\n14. Ansell SM, Kyle RA, Reeder CB, et al. Diagnosis and Management of Waldenstr\u00f6m Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines, Mayo Clin Proc 2010; 85(9): 824-833.<br \/>\n15. Varettoni M, Arcaini L, Zibellini S, et al. Prevalence and Clinical Significance of the MYD88 (L265P) Somatic Mutation in Waldenstr\u00f6m\u2019s Macroglobulinemia and Related Lymhoid Neoplasms. Blood 2013; 121(13): 2522-2528.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>*V\u0161etky tabu\u013eky, grafy a obr\u00e1zky, ktor\u00e9 s\u00fa s\u00fa\u010das\u0165ou \u010dl\u00e1nku, n\u00e1jdete v prilo\u017eenom PDF s\u00fabore na konci \u0161t\u00fadie. \u00davod Mnohopo\u010det\u00fd myel\u00f3m \u00a0(MM) patr\u00ed\u00a0 medzi hematoonkologick\u00e9 ochorenia plazmatick\u00fdch B-buniek. Vo v\u00e4\u010d\u0161ine pr\u00edpadov prevl\u00e1da v\u00fdskyt n\u00e1dorov\u00fdch buniek typu zrel\u00fdch plazmocytov s n\u00edzkou prolifera\u010dnou aktivitou. Lokaliz\u00e1cia uveden\u00fdch patologick\u00fdch foriem je striktne viazan\u00e1 na mikroprostredie kostnej drene, kde prebieha ich<\/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":[633,631,632],"class_list":["post-1029","post","type-post","status-publish","format-standard","hentry","category-genetics","tag-differential-diagnosis","tag-multiple-myeloma","tag-waldenstrom-macroglobulinemia","typ_clanku-original-work"],"acf":{"abstrakt":"<p>Multiple myeloma (MM) is a lymphoproliferative disease affecting the plasma B-lymphocytes. It is classified among monoclonal gammopathies as its major symptoms include production of monoclonal antibodies that significantly reduce the variability of the immune system. Characteristic symptoms include also osteolytic lesions, particularly in the sphere of axial skeleton, hypercalcemia and gradual failure of the renal system. The course of the disease is variable, it may start as an indolent monoclonal gammopathy of undetermined significance (MGUS) that gradually transforms into a fully-developed pathological state. Waldenstr\u00f6m macroglobulinemia (WM) represents a similar hemato-oncological malignity that also belongs among monoclonal gammopathies and comprises the sub-group of non-Hodgkin lymphoma. Symptoms and results of laboratory examinations are almost identical in both cases. To initiate a suitable therapy, it is essential to perform differential diagnosis at a molecular level.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Key words:<\/strong> multiple myeloma, Waldenstr\u00f6m macroglobulinemia, differential diagnosis<\/p>\n","casopis":[{"ID":735,"post_author":"7","post_date":"2017-04-06 13:21:01","post_date_gmt":"2017-04-06 11:21:01","post_content":"<ul>\r\n \t<li>Pseudoglandular nevus \u2013 a rare morphology of melanocytic nevus (case report)<\/li>\r\n \t<li>Differential molecular diagnosis of multiple myeloma and Waldenstr\u00f6m macroglobulinemia<\/li>\r\n \t<li>Molecular analysis of prognostically significant markers of chronic lymphocytic leukemia<\/li>\r\n \t<li>Prevalence of <em>Streptococcus pneumoniae<\/em> phyla in inflammatory diseases of upper airways in preschool age children and their resistance to antibiotics<\/li>\r\n \t<li>Malign melanoma - new aspects of research<\/li>\r\n \t<li style=\"list-style-type: none;\"><\/li>\r\n<\/ul>","post_title":"Newslab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-2017-1","to_ping":"","pinged":"","post_modified":"2017-08-16 21:11:52","post_modified_gmt":"2017-08-16 19:11:52","post_content_filtered":"","post_parent":0,"guid":"http:\/\/www.newslab.sk\/?post_type=casopis&#038;p=735\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"34","upload_clanok":{"ID":1030,"id":1030,"title":"Diferenci\u00e1lna molekulov\u00e1 diagnostika mnohopo\u010detn\u00e9ho....","filename":"Diferenci\u00e1lna-molekulov\u00e1-diagnostika-mnohopo\u010detn\u00e9ho.....pdf","filesize":822809,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2017\/04\/Diferenci\u00e1lna-molekulov\u00e1-diagnostika-mnohopo\u010detn\u00e9ho.....pdf","link":"https:\/\/www.newslab.sk\/en\/differential-molecular-diagnosis-of-multiple-myeloma-and-waldenstrom-macroglobulinemia\/diferencialna-molekulova-diagnostika-mnohopocetneho\/","alt":"","author":"7","description":"","caption":"","name":"diferencialna-molekulova-diagnostika-mnohopocetneho","status":"inherit","uploaded_to":1029,"date":"2017-04-07 12:03:15","modified":"2017-04-07 12:03:15","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\/1029","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=1029"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1029\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=1029"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=1029"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=1029"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}