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

Stáhnout PDF English version

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

Zdroje

1. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003; 121 (5): 749–757.

2. Kyle RA, Rajkumar SV. Multiple myeloma. Blood 2008; 111 (6): 2962–2972. doi: 10.1182/blood-2007-10-078022.

3. Hajek R, Krejci M, Pour L et al. Multiple myeloma. Klin Onkol 2011; 24 Suppl: S10–S13.

4. Kyle RA, Buadi F, Rajkumar SV. Management of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Oncology (Williston Park) 2011; 25 (7): 578–586.

5. Wang GL, Jiang BH, Rue EA et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer reg-ulated by cellular O2 tension. Proc Natl Acad Sci U S A 1995; 92 (12): 5510–5514.

6. Martin SK, Diamond P, Gronthos S et al. The emerging role of hypoxia, HIF-1 and HIF-2 in multiple myeloma. Leukemia 2011; 25 (10): 1533–1542. doi: 10.1038/leu.2011.122.

7. Hajek R, Okubote SA, Svachova H. Myeloma stem cell concepatients, heterogeneity and plasticity of multiple myeloma. Br J Haematol 2013; 163 (5): 551–564. doi: 10.1111/bjh.12563.

8. Colla S, Storti P, Donofrio G et al. Low bone marrow oxygen tension and hypoxia-inducible factor-1α overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138 (+) cells. Leukemia 2010; 24 (11): 1967–1970. doi: 10.1038/leu.2010.193.

9. Martin SK, Diamond P, Williams SA et al. Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells. Haematologica 2010; 95 (5): 776–784. doi: 10.3324/haematol.2009.015628.

10. Giatromanolaki A, Bai M, Margaritis D et al. Hypoxia and activated VEGF/receptor pathway in multiple myeloma. Anticancer Res 2010; 30 (7): 2831–2836.

11. Hu Y, Kirito K, Yoshida K et al. Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan. Mol Cancer Ther 2009; 8 (8): 2329–2338. doi: 10.1158/1535-7163.MCT-09-0150.

12. Borsi E, Perrone G, Terragna C et al. Hypoxia inducible factor-1 alpha as a therapeutic target in multiple myeloma. Oncotarget 2014; 5 (7): 1779–1792. doi: 10.18632/oncotarget.1736.

13. Ria R, Catacchio I, Berardi S et al. HIF-1α of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target. Clin Cancer Res 2014; 20 (4): 847–858. doi: 10.1158/1078-0432.CCR-13-1950.

14. Storti P, Bolzoni M, Donofrio G et al. Hypoxia-inducible factor (HIF) -1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction. Leukemia 2013; 27 (8): 1697–1706. doi: 10.1038/leu.2013.24.

15. Hu J, Van Valckenborgh E, Xu D et al. Synergistic induction of apoptosis in multiple myeloma cells by bortezomib and hypoxia-activated prodrug TH-302, in vivo and in vitro. Mol Cancer Ther 2013; 12 (9): 1763–1773. doi: 10.1158/1535-7163.MCT-13-0123.

16. Doublier S, Belisario DC, Polimeni M et al. HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via P-glycoprotein expression: a potential model of the chemo-resistance of invasive micropapillary carcinoma of the brest. BMC Cancer 2012; 12: 4. doi: 10.1186/1471-2407-12-4.

17. Song X, Liu X, Chi W et al. Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1alpha gene. Cancer Chemother Pharmacol 2006; 58 (6): 776–784. doi: 10.1007/s00280-006-0224-7.

18. Zhou SF, Di YM, Chan E et al. Clinical pharmacogenetics and potential application in personalized medicine. Curr Drug Metab 2008; 9 (8): 738–784.

19. Saleun JP, Vicariot M, Deroff P et al. Monoclonal gammopathies in the adult population of Finistère, France. J Clin Pathol 1982; 35 (1): 63–68.

20. Bourguet CC, Grufferman S, Delzell E et al. Multiple myeloma and family history of cancer. A case-control study. Cancer 1985; 56 (8): 2133–2139.

21. Eriksson M, Hållberg B. Familial occurrence of hematologic malignancies and other diseases in multiple myeloma: a case-control study. Cancer Causes Control 1992; 3 (1): 63–67.

22. Brown LM, Linet MS, Greenberg RS et al. Multiple myeloma and family history of cancer among blacks and whites in the U.S. Cancer 1999; 85 (11): 2385–2390.

23. Landgren O, Linet MS, McMaster ML et al. Familial characteristics of autoimmune and hematologic disorders in 8,406 multiple myeloma patients: a population-based case-control study. Int J Cancer 2006; 118 (12): 3095–3098. doi: 10.1002/ijc.21745.

24. Altieri A, Chen B, Bermejo JL et al. Familial risks and temporal incidence trends of multiple myeloma. Eur J Cancer 2006; 42 (11): 1661–1670. doi: 10.1016/j.ejca.2005.11.033.

25. Morgan G, Johnsen HE, Goldschmidt H et al. Myeloma Genetics International Consortium. Leuk Lymphoma 2012; 53 (5): 796–800. doi: 10.3109/10428194.2011.639881.

26. Almasi M, Sevcikova S, Svachova H et al. Polymorphisms contribution to the determination of significant risk of specific toxicities in multiple myeloma. Klin Okol 2011; 24 (suppl 1): S39–S42.

27. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68 (4): 978–989. doi: 10.1086/319501.

28. Stephens M, Scheet P. Accounting for decay of linkage disequilibrium in haplotype inference and missing data imputation. Am J Hum Genet 2005; 76 (3): 449–462. doi: 10.1086/428594.

29. Warnes G, Gorjanc G, Leisch F. Man M (2012) genetics: Population Genetics. [online]. Available from: http: //CRAN.R-project.org/package=genetics.

30. Rajkumar SV, Kyle RA, Therneau TM et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005; 106 (3): 812–817. doi: 10.1182/blood-2005-03-1038.

31. Broderick P, Chubb D, Johnson DC et al. Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk. Nat Genet 2011; 44 (1): 58–61. doi: 10.1038/ng.993.

32. Enciso-Mora V, Broderick P, Ma Y et al. A genome-wide association study of Hodgkin‘s lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat Genet 2010; 42 (12): 1126–1130. doi: 10.1038/ng.696.

33. Crowther-Swanepoel D, Broderick P, Di Bernardo MC et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat Genet 2010; 42 (2): 132–136. doi: 10.1038/ng.510.

34. Greenberg AJ, Lee AM, Serie DJ et al. Single-nucleotide polymorphism rs1052501 associated with monoclonal gammopathy of undetermined significance and multiple myeloma. Leukemia 2013; 27 (2): 515–516. doi: 10.1038/leu.2012.232.

35. Chubb D, Weinhold N, Broderick P et al. Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat Genet 2013; 45 (10): 1221–1225. doi: 10.1038/ng.2733.

36. Hu X, Fang Y, Zheng J et al. The association between HIF-1α polymorphism and cancer risk: a systematic review and meta-analysis. Tumour Biol 2014; 35 (2): 903–916. doi: 10.1007/s13277-013-1160-x.

37. Ruiz-Tovar J, Fernandez-Contreras ME, Martín-Perez E et al. Association of thymidylate synthase and hypoxia inducible factor-1alpha DNA polymorphisms with pancreatic cancer. Tumori 2012; 98 (3): 364–369. doi: 10.1700/1125.12406.

38. Wang X, Liu Y, Ren H et al. Polymorphisms in the hypoxia-inducible factor-1α gene confer susceptibility to pancreatic cancer. Cancer Biol Ther 2011; 12 (5): 383–387.

39. Liu J, Zhang HX 1790 G/A polymorphism, but not 1772 C/T polymorphism, is significantly associated with cancers: an update study. Gene 2013; 523 (1): 58–63. doi: 10.1016/j.gene.2013.03.129.

40. Fu SL, Miao J, Ding B et al. A polymorphism in the 3‘ untranslated region of Hypoxia-Inducible Factor-1 alpha confers an increased risk of cervical cancer in a Chinese population. Neoplasma 2013; 61 (1): 63–69. doi: 10.4149/neo_2014_002.

41. Barrett LMW, Fletcher S, Wilton SD. Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements. Cell Mol Life Sci 2012; 69 (21): 3613–34. doi: 10.1007/s00018-012-0990-9.

42. De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes 2013; 2013: 291546. doi: 10.1155/2013/291546.

43. Héron-Milhavet L, LeRoith D. Insulin-like growth factor I induces MDM2-dependent degradation of p53 via the p38 MAPK pathway in response to DNA damage. J Biol Chem 2002; 277 (18): 15600–15606. doi: 10.1074/jbc.M111142200.

44. Wu Y, Yakar S, Zhao L et al. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res 2002; 62 (4): 1030–1035.

45. Friedman GD, Herrinton LJ. Obesity and multiple myeloma. Cancer Causes Control 1994; 5 (5): 479–483.

46. Blair CK, Cerhan JR, Folsom AR et al. Anthropometric characteristics and risk of multiple myeloma. Epidemiology 2005; 16 (5): 691–694.

47. Cozen W, Gebregziabher M, Conti DV et al. Interleukin-6-related genotypes, body mass index, and risk of multiple myeloma and plasmacytoma. Cancer Epidemiol Biomarkers Prev 2006; 15 (11): 2285–2291. doi: 10.1158/1055-9965.EPI-06-0446.

48. Chiu BC, Gapstur SM, Greenland P et al. Body mass index, abnormal glucose metabolism, and mortality from hematopoietic cancer. Cancer Epidemiol Biomarkers Prev 2006; 15 (12): 2348–2354. doi: 10.1158/1055-9965.EPI-06-0007.

49. Khan MM, Mori M, Sakauchi F et al. Risk factors for multiple myeloma: evidence from the Japan Collaborative Cohort (JACC) study. Asian Pac J Cancer Prev 2006; 7 (4): 575–581.

50. Birmann BM, Giovannucci E, Rosner B et al. Body mass index, physical activity, and risk of multiple myeloma. Cancer Epidemiol Biomarkers Prev 2007; 16 (7): 1474–1478. doi: 10.1158/1055-9965.EPI-07-0143.

51. Larsson SC, Wolk A. Body mass index and risk of multiple myeloma: a meta-analysis. Int J Cancer 2007; 121 (11): 2512–2516. doi: 10.1002/ijc.22968.

52. Lichtman MA. Obesity and the risk for a hematological malignancy: leukemia, lymphoma, or myeloma. Oncologist 2010; 15 (10): 1083–1101. doi: 10.1634/theoncologist.2010-0206.

53. Wallin A, Larsson SC. Body mass index and risk of multiple myeloma: a meta-analysis of prospective studies. Eur J Cancer 2011; 47 (11): 1606–1615. doi: 10.1016/j.ejca. 2011.01.020.

54. Hofmann JN, Moore SC, Lim U et al. Body mass index and physical activity at different ages and risk of multiple myeloma in the NIH-AARP diet and health study. Am J Epidemiol 2013; 177 (8): 776–786. doi: 10.1093/aje/kws295.

55. Buda G, Ricci D, Huang CC et al. Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin. Ann Hematol 2010; 89 (11): 1133–1140. doi: 10.1007/s00277-010-0992-3.

56. Buda G, Maggini V, Galimberti S et al. MDR1 polymorphism influences the outcome of multiple myeloma patients. Br J Haematol 2007; 137 (5): 454–456. 10.1111/j.1365-2141.2007.06605.x.

57. Maggini V, Buda G, Martino A et al. MDR1 diplotypes as prognostic markers in multiple myeloma. Pharmacogenet Genomics 2008; 18 (5): 383–389. doi: 10.1097/FPC.0b013e3282f82297.

58. Jamroziak K, Balcerczak E, Calka K et al. Polymorphisms and haplotypes in the multidrug resistance 1 gene (MDR1/ABCB1) and risk of multiple myeloma. Leuk Res 2009; 33 (2): 332–335. doi: 10.1016/j.leukres.2008.06. 008.

59. Drain S, Catherwood MA, Orr N et al. ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma. Leuk Lymphoma 2009; 50 (4): 566–570. doi: 10.1080/10428190902853144.

60. Drain S, Flannely L, Drake MB et al. Multidrug resistance gene expression and ABCB1 SNPs in plasma cell myeloma. Leuk Res 2011; 35 (11): 1457–1463. doi: 10.1016/j.leukres.2011.05.033.

61. Drain S, Catherwood MA, Bjourson AJ et al. Neither P-gp SNP variants, P-gp expression nor functional P-gp activity predicts MDR in a preliminary study of plasma cell myeloma. Cytometry B Clin Cytom 2012; 82 (4): 229–237. doi: 10.1002/cyto.b.21018.