Abstract
Introduction
Vascular endothelial growth factor A (VEGFA) and its kinase insert domain receptor (VEGFR2/KDR) were reported to be upregulated in chronic myeloid leukemia (CML); however, the influence of polymorphisms in VEGFA and VEGFR2 in CML pathogenesis and therapeutic response, have not yet been elucidated.
Methods
We aimed to analyze these polymorphisms in 212 CML patients and 212 healthy controls by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach.
Results
The VEGFA+936C>T polymorphism did not differ significantly between the CML patients and controls. The frequency of CT genotype was higher in CML patients than in controls (25 vs. 18 %), higher in males than in females (29 vs. 18 %), was more prevalent in the patients with splenomegaly (p = 0.03), and was negatively associated with lactate dehydrogenase (LDH) levels (p = 0.01). The frequency of VEGFR2 mutant T-allele was higher in CML patients than controls (p < 0.0001). In the dominant model, patients having the combined AT and TT genotypes were associated with 2.6-fold higher risk of CML [odds ratio (OR) = 2.6, 95 % confidence interval (CI) = 1.71–3.97, p < 0.0001]. VEGFR2 AT genotype was significantly associated with high blast count (p = 0.006), minor hematological response (p = 0.03) and poor cytogenetic response (p = 0.003), indicating its role in therapeutic resistance. In contrast, poor molecular response was observed in patients with TT genotype (p = 0.02). VEGFA+936C>T polymorphism was found to have synergistic interaction with VEGFR2+1416A>T in inflating the risk for CML further (P interaction = 0.0002).
Conclusion
Our results indicate that VEGFR2+1416A>T polymorphism may be a useful marker in assessing the disease progression in CML patients. In addition, VEGFA+936C>T was observed to have additive effect in inflating the risk further.
Similar content being viewed by others
References
Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341:164–72.
Van Etten RA. Cellular and molecular biology of chronic myeloid leukemia (2014). http://www.uptodate.com/contents/cellular-and-molecular-biology-of-chronic-myeloid-leukemia. Accessed 1 Jun 2015.
Quintas-Cardama A, Cortes JE. Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc. 2006;81:973–88.
Jabbour E, Cortes JE, Giles FJ, O’Brien S, Kantarjian HM. Current and emerging treatment options in chronic myeloid leukemia. Cancer. 2007;109:2171–81.
Bortolheiro TC, Chiattone CS. Chronic myeloide leukemia: natural history and classification. Rev Bras Hematol Hemoter. 2008;30:3–7.
Rumpold H, Webersinke G. Molecular pathogenesis of Philadelphia-positive chronic myeloid leukemia—is it all BCR-ABL? Curr Cancer Drug Targets. 2011;11:3–19.
Bohm A, Aichberger KJ, Mayerhofer M, Herrmann H, Florian S, Krauth MT, Derdak S, Samorapoompichit P, Sonneck K, Vales A, Gleixner KV, Pickl WF, Sperr WR, Valent P. Targeting of mTOR is associated with decreased growth and decreased VEGF expression in acute myeloid leukaemia cells. Eur J Clin Investig. 2009;39:395–405.
Wimazal F, Jordan JH, Sperr WR, Chott A, Dabbass S, Lechner K, Horny HP, Valent P. Increased angiogenesis in the bone marrow of patients with systemic mastocytosis. Am J Pathol. 2002;160:1639–45.
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;2003(9):669–76.
Cao Y (2009) Positive and negative modulation of angiogenesis by VEGFR1 ligands. Sci Signal. 2009;2(59):re1–re1. doi: 10.1126/scisignal.259re1.
Katoh O, Tauchi H, Kawaishi K, Kimura A, Satow Y. Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. Cancer Res. 1995;55:5687–92.
Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D Amore PA, Dana MR, Wiegand SJ, Streilein JW. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Investig. 2004;113:1040–50.
Medinger M, Fischer N, Tzankov A. Vascular endothelial growth factor-related pathways in hemato-lymphoid malignancies. J Oncol. 2010;2010:729725. doi:10.1155/2010/729725.
Verstovsek S, Kantarjian H, Manshouri T, Cortes J, Giles FJ, Rogers A, Albitar M. Prognostic significance of cellular vascular endothelial growth factor expression in chronic phase chronic myeloid leukemia. Blood. 2002;99:2265–7.
Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D, Koller C, Estrov Z, O’Brien S, Keating M, Freireich E, Albitar M. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood. 2000;96:2240–5.
Lundberg LG, Lerner R, Sundelin P, Rogers R, Folkman J, Palmblad J. Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity. Am J Pathol. 2000;157:15–9.
Janowska-Wieczorek A, Majka M, Marquez-Curtis L, Wertheim JA, Turner AR, Ratajczak MZ. Bcr-abl-positive cells secrete angiogenic factors including matrix metalloproteinases and stimulate angiogenesis in vivo in Matrigel implants. Leukemia. 2002;16:1160–6.
Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood. 2002;100:3767–75.
Renner W, Kotschan S, Hoffmann C, Obermayer-Pietsch B, Pilger E. A common 936C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J Vasc Res. 2000;37:443–8.
Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Haas J, Samonigg H. A common 936C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. Int J Cancer. 2003;106:468–71.
Kim DH, Xu W, Kamel-Reid S, Liu X, Jung CW, Kim S, Lipton JH. Clinical relevance of vascular endothelial growth factor (VEGFA) and VEGF receptor (VEGFR2) gene polymorphism on the treatment outcome following imatinib therapy. Ann Oncol. 2010;21:1179–88.
Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 2007;19:2003–12.
Shibuya M. Vascular endothelial growth factor (VEGF)-Receptor2: its biological functions, major signaling pathway, and specific ligand VEGF-E. Endothelium. 2006;2006(13):63–9.
Verstovsek S, Lunin S, Kantarjian H, Manshouri T, Faderl S, Cortes J, Giles F, Albitar M. Clinical relevance of VEGF receptors 1 and 2 in patients with chronic myelogenous leukemia. Leuk Res. 2003;27:661–9.
Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, Flockhart DA, Hancock B, Davidson N, Gralow J, Dickler M, Perez EA, Cobleigh M, Shenkier T, Edgerton S, Miller KD, ECOG 2100. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol. 2008;26:4672–8.
Jacobs EJ, Hsing AW, Bain EB, Stevens VL, Wang Y, Chen J, Chanock SJ, Zheng SL, Xu J, Thun MJ, Calle EE, Rodriguez C. Polymorphisms in angiogenesis-related genes and prostate cancer. Cancer Epidemiol Biomark Prev. 2008;17:972–7.
Kim JG, Chae YS, Sohn SK, Cho YY, Moon JH, Park JY, Jeon SW, Lee IT, Choi GS, Jun SH. Vascular endothelial growth factor gene polymorphisms associated with prognosis for patients with colorectal cancer. Clin Cancer Res. 2008;14:62–6.
Kim DH, Lee NY, Lee MH, Sohn SK, Do YR, Park JY. Vascular endothelial growth factor (VEGF) gene (VEGFA) polymorphism can predict the prognosis in acute myeloid leukaemia patients. Br J Haematol. 2008;140:71–9.
Kim MK, Suh C, Chi HS, Cho HS, Bae YK, Lee KH, Lee GW, Kim IS, Eom HS, Kong SY, Bae SH, Ryoo HM, Shin IH, Mun YC, Chung H, Hyun MS. VEGFA and VEGFR2 genetic polymorphisms and survival in patients with diffuse large B cell lymphoma. Cancer Sci. 2012;2012(103):497–503.
Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008.
Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, Guilhot F, Hochhaus A, Horowitz M, Hughes T, Kantarjian H, Larson R, Radich J, Simonsson B, Silver RT, Goldman J, Hehlmann R, LeukemiaNet European. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;2009(27):6041–51.
Moore JH, Gilbert JC, Tsai CT, Chiang FT, Holden T, Barney N, White BC. A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol. 2006;241:252–61.
Sillaber C, Mayerhofer M, Aichberger KJ, Krauth MT, Valent P. Expression of angiogenic factors in chronic myeloid leukaemia: role of the bcr/abl oncogene, biochemical mechanisms, and potential clinical implications. Eur J Clin Investig. 2004;34:2–11.
Bachelder RE, Crago A, Chung J, Wendt MA, Shaw LM, Robinson G, Mercurio AM. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res. 2001;61:5736–40.
Harmey JH, Bouchier-Hayes D. Vascular endothelial growth factor (VEGF), a survival factor for tumour cells: implications for anti-angiogenic therapy. Bioessays. 2002;2002(24):280–3.
Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991;266:11947–54.
Kim JG, Sohn SK, Chae YS, Cho YY, Bae HI, Yan G, Park JY, Lee MH, Chung HY, Yu W. Vascular endothelial growth factor gene polymorphisms associated with prognosis for patients with gastric cancer. Ann Oncol. 2007;18:1030–6.
Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R. Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol. 2007;50:760–7.
Buysschaert I, Schmidt T, Roncal C, Carmeliet P, Lambrechts D. Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesis. J Cell Mol Med. 2008;12:2533–51.
Heist RS, Zhai R, Liu G, Zhou W, Lin X, Su L, Asomaning K, Lynch TJ, Wain JC, Christiani DC. VEGF polymorphisms and survival in early-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:856–62.
Gratzinger D, Zhao S, Tibshirani RJ, Hsi ED, Hans CP, Pohlman B, Bast M, Avigdor A, Schiby G, Nagler A, Byrne GE Jr, Lossos IS, Natkunam Y. Prognostic significance of VEGF, VEGF receptors, and microvessel density in diffuse large B cell lymphoma treated with anthracycline-based chemotherapy. Lab Investig. 2008;88:38–47.
Au WY, Caguioa PB, Chuah C, Hsu SC, Jootar S, Kim DW, Kweon IY, O’Neil WM, Saikia TK, Wang J. Chronic myeloid leukemia in Asia. Int J Hematol. 2009;89:14–23.
Sivaprasad S, Govardhan B, Harithakrishna R, Venkat Rao G, Pradeep R, Kunal B, Ramakrishna N, Anuradha S, Reddy DN. Association of vascular endothelial growth factor (VEGF) gene polymorphism and increased serum VEGF concentration with pancreatic adenocarcinoma. Pancreatology. 2013;13:267–72.
Zhao ZZ, Nyholt DR, Thomas S, Treloar SA, Montgomery GW. Polymorphisms in the vascular endothelial growth factor gene and the risk of familial endometriosis. Mol Hum Reprod. 2008;14:531–8.
Naik NA, Bhat IA, Afroze D, Rasool R, Mir H, Andrabi SI, Shah S, Siddiqi MA, Shah ZA. Vascular endothelial growth factor A gene (VEGFA) polymorphisms and expression of VEGFA gene in lung cancer patients of Kashmir Valley (India). Tumour Biol. 2012;33:833–9.
Kapahi R, Manjari M, Sudan M, Uppal MS, Singh NR, Sambyal V, Guleria K. Association of +405C>G and +936C>T polymorphisms of the vascular endothelial growth factor gene with sporadic breast cancer in North Indians. Asian Pac J Cancer Prev. 2014;15(1):257–63.
Yap RW, Shidoji Y, Hon WM, Masaki M. Association and interaction between dietary pattern and VEGF receptor-2 (VEGFR2) gene polymorphisms on blood lipids in Chinese Malaysian and Japanese adults. Asia Pac J Clin Nutr. 2012;21:302–11.
Acknowledgments
We would like to thank Ms. Rupa Sree Yedluri and Mr. Kumaraswamy Konda for their technical support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
SL, SA, AK, AVN, RRD, VKK and KJ declare no conflicts of interest.
Funding
SL, SA, AK, AVN, RRD, VKK and KJ received no funding to carry out this research study.
Ethical approval and informed consent
Institutional Ethics Committee for Biomedical Research, Bhagwan Mahavir Medical Research Centre (14, December 2011). Importance of the study was explained to all the study subjects and the informed consent was obtained.
Rights and permissions
About this article
Cite this article
Lakkireddy, S., Aula, S., Kapley, A. et al. Association of Vascular Endothelial Growth Factor A (VEGFA) and its Receptor (VEGFR2) Gene Polymorphisms with Risk of Chronic Myeloid Leukemia and Influence on Clinical Outcome. Mol Diagn Ther 20, 33–44 (2016). https://doi.org/10.1007/s40291-015-0173-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40291-015-0173-0