Abstract
Purpose
Single nucleotide polymorphisms (SNPs) in angiogenesis-associated genes might play an important role in activity of the tyrosine kinase inhibitor sunitinib and could affect survival of cancer patients treated with this drug. The aim of this retrospective study was to elucidate the role of 10 known SNPs in VEGFA, VEGFR1, VEGFR2 and VEGFR3 as potential prognostic and predictive markers in an independent cohort of patients with metastatic renal cell carcinoma (mRCC).
Methods
DNA from 121 mRCC patients treated with sunitinib was used to analyze SNPs by TaqMan genotyping assays. Disease control rate was evaluated according to RECIST. Adverse effects of sunitinib were registered from medical records. The results of Cox and logistic regression were verified by correction for multiple testing.
Results
Kaplan–Meier analysis revealed a reduced progression-free survival in patients with the wild-type (WT) allele of the VEGFA SNP rs699947 compared to variant alleles. Patients with the AA/AC-alleles of the VEGFR1 SNP rs9582036 had an improved median overall survival compared to those with the CC–WT allele what could be confirmed by multivariable Cox proportional hazard regression analyses. No statistically significant associations between the analyzed SNPs and higher risk for adverse effects were observed.
Conclusions
The results of this study suggest that most of the selected SNPs in angiogenesis-related genes are not associated with survival of mRCC patients after sunitinib therapy or with adverse effects. Only the VEGFR1 SNP rs9582036 showed a statistically significant association with overall survival. The potential of SNPs as prognostic and predictive markers for sunitinib-treated mRCC patients should be finally assessed by prospective studies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ljungberg B et al (2015) Guidelines on renal cell carcinoma. http://uroweb.org/wp-content/uploads/EAU-Guidelines-Renal-Cell-Cancer-2015-v2.pdf
Baldewijns MM, van Vlodrop IJ, Vermeulen PB, Soetekouw PM, van Engeland M, de Bruine AP (2010) VHL and HIF signalling in renal cell carcinogenesis. J Pathol 221:125–138. doi:10.1002/path.2689
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. doi:10.1093/bioinformatics/bth457
Beuselinck B et al (2013a) Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib. Br J Cancer 108:887–900. doi:10.1038/bjc.2012.548
Beuselinck B et al (2013b) VEGFR1 single nucleotide polymorphisms associated with outcome in patients with metastatic renal cell carcinoma treated with sunitinib—a multicentric retrospective analysis. Acta Oncol 53:103–112. doi:10.3109/0284186X.2013.770600
Castellano D, Ravaud A, Schmidinger M, De Velasco G, Vazquez F (2013) Therapy management with sunitinib in patients with metastatic renal cell carcinoma: key concepts and the impact of clinical biomarkers. Cancer Treat Rev 39:230–240. doi:10.1016/j.ctrv.2012.04.009
Diekstra MH et al (2015) CYP3A5 and ABCB1 polymorphisms as predictors for sunitinib outcome in metastatic renal cell carcinoma. Eur Urol 68:621–629. doi:10.1016/j.eururo.2015.04.018
Dunn OJ (1961) Multiple comparisons among means. J Am Stat Assoc 56:52–64. doi:10.1080/01621459.1961.10482090
Eechoute K et al (2012) Polymorphisms in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) predict sunitinib-induced hypertension. Clin Pharmacol Ther 92:503–510. doi:10.1038/clpt.2012.136
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN. Int J Cancer 127:2893–2917. doi:10.1002/ijc.25516
Funakoshi T, Lee CH, Hsieh JJ (2014) A systematic review of predictive and prognostic biomarkers for VEGF-targeted therapy in renal cell carcinoma Cancer Treat Rev 40:533–547. doi:10.1016/j.ctrv.2013.11.008
Garcia-Donas J et al (2011) Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol 12:1143–1150. doi:10.1016/S1470-2045(11)70266-2
Heng DY et al (2009) Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 27:5794–5799. doi:10.1200/JCO.2008.21.4809
Heng DY et al (2013) External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol 14:141–148. doi:10.1016/S1470-2045(12)70559-4
Howell WM, Bateman AC, Turner SJ, Collins A, Theaker JM (2002) Influence of vascular endothelial growth factor single nucleotide polymorphisms on tumour development in cutaneous malignant melanoma. Genes Immun 3:229–232. doi:10.1038/sj.gene.6363851
Kim DH, Lee NY, Lee MH, Sohn SK, Do YR, Park JY (2008) Vascular endothelial growth factor (VEGF) gene (VEGFA) polymorphism can predict the prognosis in acute myeloid leukaemia patients. Br J Haematol 140:71–79. doi:10.1111/j.1365-2141.2007.06887.x
Kim JJ et al (2012) Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear cell renal cell carcinoma patients treated with sunitinib. Cancer 118:1946–1954. doi:10.1002/cncr.26491
Kim HR et al (2013) Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients. Cancer Chemother Pharmacol 72:825–835. doi:10.1007/s00280-013-2258-y
Klug SJ et al (2009) TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies. Lancet Oncol 10:772–784. doi:10.1016/s1470-2045(09)70187-1
Langsenlehner T, Langsenlehner U, Renner W, Krippl P, Mayer R, Wascher TC, Kapp KS (2008) Single nucleotide polymorphisms and haplotypes in the gene for vascular endothelial growth factor and risk of prostate cancer. Eur J Cancer 44:1572–1576. doi:10.1016/j.ejca.2008.04.021
Mellado B, Gascón P (2006) Molecular biology of renal cell carcinoma. Clin Transl Oncol 8:706–710
Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, Mazumdar M (2004) Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 22:454–463. doi:10.1200/JCO.2004.06.132
Motzer RJ et al (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27:3584–3590. doi:10.1200/JCO.2008.20.1293
Motzer RJ et al (2014) Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma. Cancer Chemother Pharmacol 74:739–750. doi:10.1007/s00280-014-2539-0
Négrier S, Raymond E (2012) Antiangiogenic treatments and mechanisms of action in renal cell carcinoma. Invest New Drugs 30:1791–1801. doi:10.1007/s10637-011-9677-6
Rini BI, Atkins MB (2009) Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol 10:992–1000. doi:10.1016/S1470-2045(09)70240-2
Rodriguez S, Gaunt TR, Day IN (2009) Hardy–Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 169:505–514. doi:10.1093/aje/kwn359
Sáenz-López P, Vazquez F, Cozar JM, Carretero R, Garrido F, Ruiz-Cabello F (2013) VEGF polymorphisms are not associated with an increased risk of developing renal cell carcinoma in Spanish population. Hum Immunol 74:98–103. doi:10.1016/j.humimm.2012.10.014
Scartozzi M et al (2013) VEGF and VEGFR polymorphisms affect clinical outcome in advanced renal cell carcinoma patients receiving first-line sunitinib Br J Cancer 108:1126–1132. doi:10.1038/bjc.2012.501
Therasse P et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216
van der Veldt AA et al (2011) Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res 17:620–629. doi:10.1158/1078-0432.CCR-10-1828
van Erp NP et al (2009) Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol 27:4406–4412. doi:10.1200/JCO.2008.21.7679
Yuasa T, Takahashi S, Hatake K, Yonese J, Fukui I (2011) Biomarkers to predict response to sunitinib therapy and prognosis in metastatic renal cell cancer. Cancer Sci 102:1949–1957. doi:10.1111/j.1349-7006.2011.02054.x
Acknowledgments
We thank the German Renal Cell Cancer Network for the successful cooperation and Kati Erdmann for her critical review of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Written informed consent was obtained from all individual participants included in the study.
Additional information
On behalf of the German Renal Cell Cancer Network.
Rights and permissions
About this article
Cite this article
Dornbusch, J., Walter, M., Gottschalk, A. et al. Evaluation of polymorphisms in angiogenesis-related genes as predictive and prognostic markers for sunitinib-treated metastatic renal cell carcinoma patients. J Cancer Res Clin Oncol 142, 1171–1182 (2016). https://doi.org/10.1007/s00432-016-2137-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-016-2137-0