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Genetic polymorphisms and multiple myeloma risk: a meta-analysis

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Abstract

Previous researches exploring associations between multiple myeloma (MM) and genetic polymorphisms showed controversial results. In this investigation, we aimed to make a meta-analysis to assess the association between MM risk and genetic polymorphisms. We searched for articles on genetic polymorphism and MM risk in Web of Science and PubMed databases from 1951 to August 2019. We computed the odds ratio (OR) and 95% confidence intervals (CI) extracted from included articles. The meta-analysis showed no significant associations between MM risks and tumor necrosis factor (TNF)-α (rs1800629/rs361525/rs1799724), interleukin (IL)-6 (rs1800795), multidrug resistance 1 (MDR1) (rs1045642), Methylenetetrahydrofolate reductase (MTHFR) (rs1801131/rs1801133) polymorphisms. In summary, the study shows that the TNF-α (rs1800629/rs361525/rs1799724), IL-6 (rs1800795), MDR1 (rs1045642), and MTHFR (rs1801131/rs1801133) polymorphisms may not be associated with MM susceptibility. Thus, we do not need more expensive and useless studies to explore the associations between MM risks and these genetic polymorphisms.

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References

  1. Palumbo A, Anderson K (2011) Multiple myeloma. N Engl J Med 364(11):1046–1060. https://doi.org/10.1056/NEJMra1011442

    Article  CAS  PubMed  Google Scholar 

  2. Brigle K, Rogers B (2017) Pathobiology and diagnosis of multiple myeloma. Semin Oncol Nurs 33(3):225–236. https://doi.org/10.1016/j.soncn.2017.05.012

    Article  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30. https://doi.org/10.3322/caac.21442

    Article  PubMed  Google Scholar 

  4. Alexander DD, Mink PJ, Adami HO, Cole P, Mandel JS, Oken MM, Trichopoulos D (2007) Multiple myeloma: a review of the epidemiologic literature. Int J Cancer 120(Suppl 12):40–61. https://doi.org/10.1002/ijc.22718

    Article  CAS  PubMed  Google Scholar 

  5. Basmaci C, Pehlivan M, Tomatir A, Sever T, Okan V, Yilmaz M, Oguzkan-Balci S, Pehlivan S (2016) Effects of TNFalpha, NOS3, MDR1 gene polymorphisms on clinical parameters, prognosis and survival of multiple myeloma cases. Asian Pac J Cancer Prev 17(3):1009–1014

    Article  CAS  PubMed  Google Scholar 

  6. Du J, Yuan Z, Zhang C, Fu W, Jiang H, Chen B, Hou J (2010) Role of the TNF-alpha promoter polymorphisms for development of multiple myeloma and clinical outcome in thalidomide plus dexamethasone. Leuk Res 34(11):1453–1458. https://doi.org/10.1016/j.leukres.2010.01.011

    Article  CAS  PubMed  Google Scholar 

  7. Iakupova EV, Grinchuk OV, Kalimullina D, Bakirov BA, Galimova RR, Makarova OV, Khusnutdinova EK, Viktorova TV (2003) Molecular genetic analysis of the interleukin 6 and tumor necrosis factor alpha gene polymorphisms in multiple myeloma. Mol Biol 37(3):420–424

    CAS  Google Scholar 

  8. Morgan GJ, Adamson PJ, Mensah FK, Spink CF, Law GR, Keen LJ, Roman E, Davies FE, Rollinson S, Child JA, Bidwell JL (2005) Haplotypes in the tumour necrosis factor region and myeloma. Br J Haematol 129(3):358–365. https://doi.org/10.1111/j.1365-2141.2005.05467.x

    Article  CAS  PubMed  Google Scholar 

  9. Nielsen KR, Rodrigo-Domingo M, Steffensen R, Baech J, Bergkvist KS, Oosterhof L, Schmitz A, Bodker JS, Johansen P, Vogel U, Vangsted A, Dybkaer K, Bogsted M, Johnsen HE (2017) Interactions between SNPs affecting inflammatory response genes are associated with multiple myeloma disease risk and survival. Leuk Lymphoma 58(11):2695–2704. https://doi.org/10.1080/10428194.2017.1306643

    Article  CAS  PubMed  Google Scholar 

  10. Zheng C, Huang DR, Bergenbrant S, Sundblad A, Osterborg A, Bjorkholm M, Holm G, Yi Q (2000) Interleukin 6, tumour necrosis factor alpha, interleukin 1beta and interleukin 1 receptor antagonist promoter or coding gene polymorphisms in multiple myeloma. Br J Haematol 109(1):39–45

    Article  CAS  PubMed  Google Scholar 

  11. Aladzsity I, Kovacs M, Semsei A, Falus A, Szilagyi A, Karadi I, Varga G, Fust G, Varkonyi J (2009) Comparative analysis of IL6 promoter and receptor polymorphisms in myelodysplasia and multiple myeloma. Leuk Res 33(11):1570–1573. https://doi.org/10.1016/j.leukres.2009.03.009

    Article  CAS  PubMed  Google Scholar 

  12. Birmann BM, Tamimi RM, Giovannucci E, Rosner B, Hunter DJ, Kraft P, Mitsiades C, Anderson KC, Colditz GA (2009) Insulin-like growth factor-1- and interleukin-6-related gene variation and risk of multiple myeloma. Cancer Epidemiol Biomarkers Prev 18(1):282–288. https://doi.org/10.1158/1055-9965.epi-08-0778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chakraborty B, Vishnoi G, Gowda SH, Goswami B (2017) Interleukin-6 gene-174 G/C promoter polymorphism and its association with clinical profile of patients with multiple myeloma. Asia Pac J Clin Oncol 13(5):e402–e407. https://doi.org/10.1111/ajco.12290

    Article  PubMed  Google Scholar 

  14. Duch CR, Figueiredo MS, Ribas C, Almeida MS, Colleoni GW, Bordin JO (2007) Analysis of polymorphism at site −174 G/C of interleukin-6 promoter region in multiple myeloma. Braz J Med Biol Res 40(2):265–267

    Article  CAS  PubMed  Google Scholar 

  15. Mazur G, Bogunia-Kubik K, Wrobel T, Karabon L, Polak M, Kuliczkowski K, Lange A (2005) IL-6 and IL-10 promoter gene polymorphisms do not associate with the susceptibility for multiple myeloma. Immunol Lett 96(2):241–246. https://doi.org/10.1016/j.imlet.2004.08.015

    Article  CAS  PubMed  Google Scholar 

  16. Drain S, Catherwood MA, Orr N, Galligan L, Rea IM, Hodkinson C, Drake MB, Kettle PJ, Morris TC, Alexander HD (2009) ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma. Leuk Lymphoma 50(4):566–570. https://doi.org/10.1080/10428190902853144

    Article  CAS  PubMed  Google Scholar 

  17. Jamroziak K, Balcerczak E, Calka K, Piaskowski S, Urbanska-Rys H, Salagacka A, Mirowski M, Robak T (2009) Polymorphisms and haplotypes in the multidrug resistance 1 gene (MDR1/ABCB1) and risk of multiple myeloma. Leuk Res 33(2):332–335. https://doi.org/10.1016/j.leukres.2008.06.008

    Article  CAS  PubMed  Google Scholar 

  18. Yin G, Xiao Z, Ni Y, Qu X, Wu H, Lu H, Qian S, Chen L, Li J, Qiu H, Miao K (2016) Association of MDR1 single-nucleotide polymorphisms and haplotype variants with multiple myeloma in Chinese Jiangsu Han population. Tumour Biol 37(7):9549–9554. https://doi.org/10.1007/s13277-015-4574-9

    Article  CAS  PubMed  Google Scholar 

  19. Chiusolo P, Farina G, Putzulu R, Reddiconto G, Fiorini A, De Stefano V, Rossi E, Palladino M, Leone G, Sica S (2006) Analysis of MTHFR polymorphisms and P16 methylation and their correlation with clinical-biological features of multiple myeloma. Ann Hematol 85(7):474–477. https://doi.org/10.1007/s00277-006-0097-1

    Article  CAS  PubMed  Google Scholar 

  20. Gonzalez-Fraile MI, Garcia-Sanz R, Mateos MV, Balanzategui A, Gonzalez M, Vaquez L, San Miguel JF (2002) Methylenetetrahydrofolate reductase genotype does not play a role in multiple myeloma pathogenesis. Br J Haematol 117(4):890–892

    Article  CAS  PubMed  Google Scholar 

  21. Hatzimichael E, Dasoula A, Benetatos L, Syed N, Dranitsaris G, Crook T, Bourantas K (2010) Study of specific genetic and epigenetic variables in multiple myeloma. Leuk Lymphoma 51(12):2270–2274. https://doi.org/10.3109/10428194.2010.528095

    Article  CAS  PubMed  Google Scholar 

  22. Jiang N, Zhu X, Zhang H, Wang X, Zhou X, Gu J, Chen B, Ren J (2014) The relationship between methylenetetrahydrofolate reductase polymorphism and hematological malignancy. Clin Lab 60(5):767–774

    CAS  PubMed  Google Scholar 

  23. Lima CS, Ortega MM, Ozelo MC, Araujo RC, De Souza CA, Lorand-Metze I, Annichino-Bizzacchi JM, Costa FF (2008) Polymorphisms of methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and thymidylate synthase (TYMS) in multiple myeloma risk. Leuk Res 32(3):401–405. https://doi.org/10.1016/j.leukres.2007.06.001

    Article  CAS  PubMed  Google Scholar 

  24. Lincz LF, Scorgie FE, Kerridge I, Potts R, Spencer A, Enno A (2003) Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B-cell non-Hodgkin’s lymphoma or multiple myeloma. Br J Haematol 120(6):1051–1054

    Article  CAS  PubMed  Google Scholar 

  25. Moon HW, Kim TY, Oh BR, Min HC, Cho HI, Bang SM, Lee JH, Yoon SS, Lee DS (2007) MTHFR 677CC/1298CC genotypes are highly associated with chronic myelogenous leukemia: a case-control study in Korea. Leuk Res 31(9):1213–1217. https://doi.org/10.1016/j.leukres.2006.10.016

    Article  CAS  PubMed  Google Scholar 

  26. Gonzalez Ordonez AJ, Fernandez Carreira JM, Fernandez Alvarez CR, Martin L, Sanchez Garcia J, Medina Rodriguez JM, Alvarez MV, Coto E (2000) Normal frequencies of the C677T genotypes on the methylenetetrahydrofolate reductase (MTHFR) gene among lymphoproliferative disorders but not in multiple myeloma. Leuk Lymphoma 39(5–6):607–612. https://doi.org/10.3109/10428190009113391

    Article  CAS  PubMed  Google Scholar 

  27. Martino A, Campa D, Jurczyszyn A, Martinez-Lopez J, Moreno MJ, Varkonyi J, Dumontet C, Garcia-Sanz R, Gemignani F, Jamroziak K, Stepiel A, Jacobsen SE, Andersen V, Jurado M, Landi S, Rossi AM, Lesueur F, Marques H, Dudzinski M, Watek M, Moreno V, Orciuolo E, Petrini M, Reis RM, Rios R, Sainz J, Vogel U, Buda G, Vangsted AJ, Canzian F (2014) Genetic variants and multiple myeloma risk: IMMEnSE validation of the best reported associations--an extensive replication of the associations from the candidate gene era. Cancer Epidemiol Biomark Prev 23(4):670–674. https://doi.org/10.1158/1055-9965.epi-13-1115

    Article  CAS  Google Scholar 

  28. Despotovic M, Stoimenov TJ, Stankovic I, Pavlovic D, Sokolovic D, Cvetkovic T, Kocic G, Basic J, Veljkovic A, Djordjevic B (2015) Gene polymorphisms of tumor necrosis factor alpha and antioxidant enzymes in bronchial asthma. Adv Clin Exp Med 24(2):251–256. https://doi.org/10.17219/acem/40454

    Article  PubMed  Google Scholar 

  29. Zins K, Abraham D, Sioud M, Aharinejad S (2007) Colon cancer cell-derived tumor necrosis factor-alpha mediates the tumor growth-promoting response in macrophages by up-regulating the colony-stimulating factor-1 pathway. Cancer Res 67(3):1038–1045. https://doi.org/10.1158/0008-5472.can-06-2295

    Article  CAS  PubMed  Google Scholar 

  30. Zhu G, Du Q, Wang X, Tang N, She F, Chen Y (2014) TNF-alpha promotes gallbladder cancer cell growth and invasion through autocrine mechanisms. Int J Mol Med 33(6):1431–1440. https://doi.org/10.3892/ijmm.2014.1711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kulbe H, Thompson R, Wilson JL, Robinson S, Hagemann T, Fatah R, Gould D, Ayhan A, Balkwill F (2007) The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res 67(2):585–592. https://doi.org/10.1158/0008-5472.can-06-2941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Klein B, Zhang XG, Lu ZY, Bataille R (1995) Interleukin-6 in human multiple myeloma. Blood 85(4):863–872

    Article  CAS  PubMed  Google Scholar 

  33. Rawstron AC, Fenton JA, Ashcroft J, English A, Jones RA, Richards SJ, Pratt G, Owen R, Davies FE, Child JA, Jack AS, Morgan G (2000) The interleukin-6 receptor alpha-chain (CD126) is expressed by neoplastic but not normal plasma cells. Blood 96(12):3880–3886

    Article  CAS  PubMed  Google Scholar 

  34. Chong PSY, Chng WJ, de Mel S (2019) STAT3: a promising therapeutic target in multiple myeloma. Cancers 11(5). https://doi.org/10.3390/cancers11050731

  35. Chong PSY, Zhou J, Lim JSL, Hee YT, Chooi JY, Chung TH, Tan TZ, Zeng Q, Waller DD, Sebag M, Chng WJ (2019) Interleukin-6 promotes a STAT3-PRL3 feedforward loop via SHP2 repression in multiple myeloma. Cancer Res. https://doi.org/10.1158/0008-5472.can-19-0343

  36. Peng X, Shi J, Sun W, Ruan X, Guo Y, Zhao L, Wang J, Li B (2018) Genetic polymorphisms of IL-6 promoter in cancer susceptibility and prognosis: a meta-analysis. Oncotarget 9(15):12351–12364. https://doi.org/10.18632/oncotarget.24033

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zhai X, Wang H, Zhu X, Miao H, Qian X, Li J, Gao Y, Lu F, Wu Y (2012) Gene polymorphisms of ABC transporters are associated with clinical outcomes in children with acute lymphoblastic leukemia. Arch Med Sci 8(4):659–671. https://doi.org/10.5114/aoms.2012.30290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kimura Y, Morita SY, Matsuo M, Ueda K (2007) Mechanism of multidrug recognition by MDR1/ABCB1. Cancer Sci 98(9):1303–1310. https://doi.org/10.1111/j.1349-7006.2007.00538.x

    Article  CAS  PubMed  Google Scholar 

  39. Tsubaki M, Satou T, Itoh T, Imano M, Komai M, Nishinobo M, Yamashita M, Yanae M, Yamazoe Y, Nishida S (2012) Overexpression of MDR1 and survivin, and decreased Bim expression mediate multidrug-resistance in multiple myeloma cells. Leuk Res 36(10):1315–1322. https://doi.org/10.1016/j.leukres.2012.07.003

    Article  CAS  PubMed  Google Scholar 

  40. Besse A, Stolze SC, Rasche L, Weinhold N, Morgan GJ, Kraus M, Bader J, Overkleeft HS, Besse L, Driessen C (2018) Carfilzomib resistance due to ABCB1/MDR1 overexpression is overcome by nelfinavir and lopinavir in multiple myeloma. Leukemia 32(2):391–401. https://doi.org/10.1038/leu.2017.212

    Article  CAS  PubMed  Google Scholar 

  41. Razi B, Anani Sarab G, Omidkhoda A, Alizadeh S (2018) Multidrug resistance 1 (MDR1/ABCB1) gene polymorphism (rs1045642 C > T) and susceptibility to multiple myeloma: a systematic review and meta-analysis. Hematology 23(8):456–462. https://doi.org/10.1080/10245332.2018.1443897

    Article  CAS  PubMed  Google Scholar 

  42. Niebudek K, Balcerczak E, Mirowski M, Zebrowska M (2018) Association of ABCB1 T-129C polymorphism and multiple myeloma risk in Polish population. Pol J Pathol 69(4):405–409. https://doi.org/10.5114/pjp.2018.81700

    Article  PubMed  Google Scholar 

  43. Rosenblatt DS (2001) Methylenetetrahydrofolate reductase. Clin Invest Med 24(1):56–59

    CAS  PubMed  Google Scholar 

  44. Duthie SJ (2011) Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis 34(1):101–109. https://doi.org/10.1007/s10545-010-9128-0

    Article  CAS  PubMed  Google Scholar 

  45. Gaughan DJ, Barbaux S, Kluijtmans LA, Whitehead AS (2000) The human and mouse methylenetetrahydrofolate reductase (MTHFR) genes: genomic organization, mRNA structure and linkage to the CLCN6 gene. Gene 257(2):279–289. https://doi.org/10.1016/s0378-1119(00)00392-9

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Lihua Gu (a doctor in Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China) helped to read abstracts and full-texts.

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Zhang, P., Liu, B. Genetic polymorphisms and multiple myeloma risk: a meta-analysis. Ann Hematol 99, 1017–1024 (2020). https://doi.org/10.1007/s00277-020-03979-7

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