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Annals of Oncology Advance Access published online on October 29, 2009
Annals of Oncology, doi:10.1093/annonc/mdp452
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Clinical relevance of vascular endothelial growth factor (VEGFA) and VEGF receptor (VEGFR2) gene polymorphism on the treatment outcome following imatinib therapy

D. H. Kim1,2,*, W. Xu3, S. Kamel-Reid4, X. Liu5, C. W. Jung2, S. Kim6 and J. H. Lipton1

1 Department of Hematology/Medical Oncology, Chronic Myelogenous Leukemia Group, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
2 Department of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
3 Department of Biostatistics, Princess Margaret Hospital
4 Department of Pathology
5 Analytical Genetics Technology Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
6 Biostatistics, Samsung Biomedical Research Institute, Seoul, Korea

* Correspondence to: Dr D. H. Kim, Department of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Ilwon-dong 50, Kangnam-gu, Seoul 135-710, Korea. Tel: +82-2-3410-3459; Fax: +82-2-3410-0041; E-mail: drkiim{at}medimail.co.kr

Background: Imatinib could reverse marrow angiogenesis and decrease the plasma level of vascular endothelial growth factor (VEGF) in chronic myeloid leukemia (CML) patients.

Methods, materials and patients: The current study investigated the impact of four vascular endothelial growth factor type A (VEGFA) and three vascular endothelial growth factor receptor type 2 (VEGFR2) gene polymorphisms on the outcomes of 228 CML patients following imatinib therapy. VEGFA genotypes such as –2578C>A (rs699947), –460T>C (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) loci and VEGFR2 genotypes (rs1531289, rs1870377 and rs2305948) were analyzed using matrix-assisted laser desorption/ionization time-of-flight-based method.

Results: In single marker analyses, strong correlations were noted between complete cytogenetic response (CCyR) and VEGFR2 genotypes (rs1531289/rs1870377), between treatment failure and VEGFR2 genotype (rs1870377) and between progression to advanced disease and VEGFA genotypes (rs699947/rs833061). Three haplotypes of VEGFR2 gene were generated as follows: GT (46.1%), AT (27.9%) and GA (25.7%). Haplotype analyses showed good correlations between VEGFR2 haplotype and CCyR and treatment failure to imatinib. Multivariate analyses confirmed strong correlations of VEGFR2 polymorphisms (especially rs1531289, rs1870377 or VEGFR2 haplotype) with CCyR, treatment failure and of VEGFA genotype (rs699947) with progression to advanced disease.

Conclusion: The VEGFR2 gene polymorphism correlates with cytogenetic response, treatment failure following imatinib therapy for CML, while VEGFA genotype correlates with progression to advanced disease.

angiogenesis, chronic myeloid leukemia, imatinib mesylate, single-nucleotide polymorphism, VEGF, VEGFR2

Received for publication March 12, 2009. Revision received July 15, 2009. Accepted for publication August 7, 2009.


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