Abstract
Angiogenesis has been highlighted as a critical component in the progression of multiple myeloma (MM), and vascular endothelial growth factor (VEGF) as well as its type 2 receptor (VEGFR2) are thought to play a major role in the process. Single nucleotide polymorphisms (SNPs) have been described in VEGF and VEGFR2 genes, with quantitative or qualitative changes in encoded VEGF and VEGFR2. The roles of VEGF −2578C/A, −1154G/A, and −634G/C as well as VEGFR2 −604T/C and +1192G/A SNPs in the risk and manifestations of MM are still unknown; therefore, this study aimed to clarify this issue. DNA from 192 patients and 209 controls were analyzed by real-time polymerase chain reaction for identification of genotypes. The frequencies of VEGF −2578CC, VEGF −2578CC plus VEGF −634GG, and VEGF −2578CC plus VEGF −1154GG plus VEGF −634GG genotypes were higher in patients than in controls. Carriers of the respective genotypes had a 1.89-, a 5.52-, and a 4.91-fold increased risk for MM than others. VEGF −2578CC plus VEGFR2 +1192GG, VEGF −2578CC plus VEGF −634GG plus VEGFR2 +1192GG, and VEGF −1154GG plus VEGF −634GG plus VEGFR2 −604TT combined genotypes were more common in patients than in controls. Carriers of the respective genotypes had a 2.56-, a 10.97-, and a 14.10-fold increased risk for MM than others. An excess of VEGFR2 −604TT genotype was also seen in patients with stage II or III tumors when compared with those with stage I tumors. Our data suggest, for the first time, that inherited abnormalities in VEGF and VEGFR2 pathways influence the risk and aggressiveness of MM.
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References
Moehler TM, Neben K, Ho AD, Goldschmidt H (2001) Angiogenesis in hematologic malignancies. Ann Hematol 80(12):695–705
Giuliani N, Storti P, Bolzoni M, Palma BD, Bonomini S (2011) Angiogenesis and multiple myeloma. Cancer Microenviron 4(3):325–337
Gille H, Kowalski J, Li B, Le Couter J, Moffat B, Zioncheck TF, Pelletier N, Ferrara N (2001) Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). J Biol Chem 276(5):3222–3230
Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT, Lin B, Lentzsch S, Davies FE, Chauhan D, Schlossman RL, Richardson P, Ralph P, Wu L, Payvandi F, Muller G, Stirling DI, Anderson KC (2001) Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 15(12):1950–1961
Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Fonseca R, Greipp PR, Rajkumar SV (2003) Expression of VEGF and its receptors by myeloma cells. Leukemia 17(10):2025–2031
Ria R, Roccaro AM, Merchionne F, Vacca A, Dammacco F, Ribatti D (2003) Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia 17(10):1961–1966
Dankbar B, Padró T, Leo R, Feldmann B, Kropff M, Mesters RM, Serve H, Berdel WE, Kienast J (2000) Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 95(8):2630–2636
Brogan IJ, Khan N, Isaac K, Hutchinson JA, Pravica V, Hutchinson IV (1999) Novel polymorphisms in the promoter and 5′ UTR regions of the human vascular endothelial growth factor gene. Hum Immunol 60(12):1245–1249
Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE (2000) Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine 12(8):1232–1235
Shahbazi M, Fryer AA, Pravica V, Brogan IJ, Ramsay HM, Hutchinson IV, Harden PN (2002) Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol 13(1):260–264
Steffensen KD, Waldsstrom M, Brandslund I, Jakobsen A (2010) The relationship of VEGF polymorphisms with serum VEGF levels and progression-free survival in patients with epithelial ovarian cancer. Gynecol Oncol 117(1):109–116
Kariyazono H, Ohno T, Khajoee V, Ihara K, Kusuhara K, Kinukawa N, Mizuno Y, Hara T (2004) Association of vascular endothelial growth factor (VEGF) and VEGF receptor gene polymorphisms with coronary artery lesions of Kawasaki disease. Pediatr Res 56(6):953–959
Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R (2007) Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol 50(8):760–767
Belon AP, Barros MB (2011) Life expectancy at birth: impact of variation in mortality by age group and cause of death in Campinas, São Paulo State. Brazil Cad Saude Publica 27(5):877–887
Kyle RA, Rajkumar SV (2009) Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 23(1):3–9
Durie BG, Salmon SE (1975) A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer 36(3):842–854
Kämmerer PW, Toyoshima T, Eletr S, Kämmerer P, Kuhr K, Al-Nawas B, Brieger J (2010) Single nucleotide polymorphisms of the vascular endothelial growth factor gene associated with incidence of oral squamous cell carcinoma. J Oral Pathol Med 39(10):786–792
Wang K, Liu L, Zhu ZM, Shao JH, Xin L (2011) Five polymorphisms of vascular endothelial growth factor (VEGF) and risk of breast cancer: a meta-analysis involving 16,703 individuals. Cytokine 56(2):167–173
Chen H, Wang W, Xingjie Z, Song X, Fan W, Keke Z, Chen G, Zhao Y, Mao Y, Lu D (2012) Association between genetic variations of vascular endothelial growth factor receptor 2 and glioma in the Chinese Han population. J Mol Neurosci 47(3):448–457
Jang MJ, Jeon YJ, Kim JW, Cho YK, Lee SK, Hwang SG, Oh D, Kim NK (2013) Association of VEGF and KDR single nucleotide polymorphisms with colorectal cancer susceptibility in Koreans. Mol Carcinog 52(1):60–69
Lin L, Cao K, Chen W, Pan X, Zhao H (2013) Four common vascular endothelial growth factor polymorphisms (−2578C > A, −460C > T, +936C > T, and +405G > C) in susceptibility to lung cancer: a meta-analysis. PLoS One 8(10):e75123
Galimberti S, Nagy B, Palumbo GA, Ciancia E, Buda G, Orciuolo E, Melosi A, Lambelet P, Ronca F, Petrini (2010) Vascular endothelial growth factor polymorphisms in mantle cell lymphoma. Acta Haematol 123(2):91–95
Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5):1011–1027
Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES (2011) High-resolution haplotype structure in the human genome. Nat Genet 29(2):229–232
Niemöller K, Jakob C, Heider U, Zavrski I, Eucker J, Kaufmann O, Possinger K, Sezer O (2003) Bone marrow angiogenesis and its correlation with other disease characteristics in multiple myeloma in stage I versus stage II-III. J Cancer Res Clin Oncol 129(4):234–238
Rajkumar SV, Leong T, Roche PC, Fonseca R, Dispenzieri A, Lacy MQ, Lust JA, Witzig TE, Kyle RA, Gertz MA, Greipp PR (2000) Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 6(8):3111–3116
Andersen NF, Vogel U, Klausen TW, Gimsing P, Gregersen H, Abildgaard N, Vangsted AJ (2012) Vascular endothelial growth factor (VEGF) gene polymorphisms may influence the efficacy of thalidomide in multiple myeloma. Int J Cancer 131(5):E636–E642
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Brito, A.B.C., Lourenço, G.J., Oliveira, G.B. et al. Associations of VEGF and VEGFR2 polymorphisms with increased risk and aggressiveness of multiple myeloma. Ann Hematol 93, 1363–1369 (2014). https://doi.org/10.1007/s00277-014-2062-8
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DOI: https://doi.org/10.1007/s00277-014-2062-8