Vybrané genetické polymorfizmy asociované s hypoxií a multilékovou rezistencí u pacientů s monoklonálními gamapatiemi
Authors:
Almasi Martina 1; Besse Lenka 2; Brozova Lucie 3; Jarkovsky Jiri 3; Bezdekova Renata 1; Pour Ludek 4; Minarik Jiri 5; Kessler Petr 6; Pavlicek Petr 7; Roziakova Lubica 8; Penka Miroslav 1; Hájek Roman 1,9; Vasku Anna 10; Sevcikova Sabina 1,11
Authors‘ workplace:
Department of Clinical Hematology, University Hospital Brno, Brno, Czech Republic
1; Department of Oncology and Hematology, Cantonal Hospital St. Gallen, Switzerland
2; Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic
3; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine Masaryk University, Brno, Czech Republic 5 Department of Hematooncology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky
4; Department of Hematology and Transfusion Medicine, Hospital Pelhrimov, Pelhřimov, Czech Republic
6; Department for Internal Medicine and Haematology, 3rd Faculty of Medicine, Charles University in Prague and Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic
7; Department of Hematology and Transfusion Medicine, University Hospital, School of Medicine, Comenius University Bratislava, Slovak Republic
8; Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
9; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
10; Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
11
Published in:
Klin Onkol 2018; 31(3): 213-229
Category:
Original Articles
doi:
https://doi.org/10.14735/amko2018213
Overview
Východiska:
Přirozená reakce organizmu na hypoxii je regulována různými mechanizmy a transkripčními faktory, zahrnujícími hypoxií indukovatelné faktory (HIFs). Aktivace HIF-1α je u nádorových buněk spojována se zvýšenou expresí P-glykoproteinu a multilékovou rezistencí. V této retrospektivní analýze jsme sledovali kandidátní jednonukleotidové polymorfizmy (single-nucleotide polymorphisms – SNP) genů HIF-1α a HIF-1β a jejich spojení s rizikem vzniku onemocnění monoklonální gamapatie nejasného významu (monoclonal gammopathy of undetermined significance – MGUS) nebo mnohočetného myelomu (MM).
Soubor pacientů a metody:
Genotypy jednonukleotidových polymorfizmů spojovaných s hypoxií byly určovány pomocí real time polymerázové řetězové reakce alelické diskriminace u nezávislé skupiny pacientů s monoklonální gamapatií (MG) (275 pacientů s MM a 228 s MGUS) a u 219 kontrol bez nádorového onemocnění.
Výsledky:
Při porovnání pacientů s MM a kontrol jsme pozorovali příznivější vliv genotypu CG genu HIF-1β (rs2228099) oproti genotypu CC (OR 0,65; CI 0,45–0,95; p = 0,026). Obdobně i při zohlednění věku pacientů a jejich indexu tělesné hmotnosti byla signifikantně nižší šance (OR 0,55; p = 0,045) rozvoje onemocnění MM u genotypu CG oproti CC. Log-rank test potvrdil souvislost GT haplotypu (rs11549467, rs2057482) genu HIF-1α s lepším celkovým přežitím (medián 41,8 měsíce; (CI 35,1–48,5) u haplotypu „žádné GT“ a medián 93,8 měsíce (CI 31,3–156,4) u haplotypu „nejméně jeden GT“ (p = 0,0500). Dále byla zjištěna významná souvislost mezi jednonukleotidovými polymorfizmy v genu MDR1 a léčebným účinkem u 110 pacientů s MM léčených bortezomibem.
Závěr:
Naše studie ukázala možnou genetickou predispozici k riziku rozvoje MG a/nebo k léčebné odpovědi pacientů s MM, nicméně je třeba provést další studie k potvrzení naší počáteční analýzy.
Klíčová slova:
mnohočetný myelom – hypoxie – genotype – polymorfizmus – qPCR
Tato práce byla podpořena projektem MZ ČR FNBr, 65269705.
Autoři deklarují, že v souvislosti s předmětem nemají žádné komerční zájmy.
Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů.
Obdrženo: 19. 3. 2018
Přijato: 24. 4. 2018
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