Vybrané genetické polymorfizmy asociované s hypoxií a multilékovou rezistencí u pacientů s monoklonálními gamapatiemi

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Autoři: 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
Působiště autorů: 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
Vyšlo v časopise: Klin Onkol 2018; 31(3): 213-229
Kategorie: Původní práce
doi: https://doi.org/10.14735/amko2018213

Souhrn

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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