Advertisement

Angiogenesis

, Volume 22, Issue 3, pp 433–440 | Cite as

Prognostic effect of VEGF gene variants in metastatic non-small-cell lung cancer patients

  • Ivana SullivanEmail author
  • Pau Riera
  • Marta Andrés
  • Albert Altés
  • Margarita Majem
  • Remei Blanco
  • Laia Capdevila
  • Andrés Barba
  • Agustí Barnadas
  • Juliana SalazarEmail author
Original Paper

Abstract

Introduction

Clinical and pathological characteristics are still considered prognostic markers in metastatic non-small-cell lung cancer (NSCLC) patients but they cannot explain all interindividual variability. Tumoral angiogenesis mediated by the vascular endothelial growth factor (VEGF) is critical for the progression and metastasis of the disease. We aimed to investigate the prognostic role of genetic variants within the VEGF pathway in patients with metastatic NSCLC.

Materials and methods

We prospectively included 170 patients with metastatic NSCLC treated with first-line platinum-based chemotherapy. A comprehensive panel of single-nucleotide polymorphisms (SNPs) in genes belonging to the VEGF pathway (VEGFA, VEGFR1/FLT1, VEGFR2/KDR, GRB2, ITGAV, KISS1, KRAS, PRKCE, HIF1α, MAP2K4, MAP2K6, and MAPK11) were genotyped in blood DNA samples. SNPs were evaluated for association with overall survival (OS) and progression-free survival (PFS).

Results

In multivariate analyses adjusted for patient characteristics, we found that VEGFA rs2010963 and VEGFR2 rs2071559 were significantly associated with OS [Hazard Ratio (HR) 0.7 (0.5–0.9); p = 0.026 and HR 1.5 (1.1–2.3); p = 0.025, respectively]. Additionally, ITGAV rs35251833 and MAPK11 rs2076139 were significantly associated with PFS [HR 2.5 (1.4–4.3; p = 0.002 and HR 0.6 (0.5–0.9); p = 0.013, respectively].

Conclusion

Our findings reinforce the potential clinical value of germline variants in VEGFA and VEGFR2 and show for the first time variants in ITGAV and MAPK11 as promising prognostic markers in metastatic NSCLC patients receiving platinum-based chemotherapy.

Keywords

VEGF Genetic variants Metastatic NSCLC Prognostic factors 

Notes

Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We thank Carolyn Newey for language editing.

Compliance with ethical standards

Conflict of interest

The authors declared no conflict of interest.

Supplementary material

10456_2019_9668_MOESM1_ESM.docx (35 kb)
Supplementary material 1 (DOCX 34 kb)

References

  1. 1.
    Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2016. CA Cancer J Clin 66(1):7–30CrossRefGoogle Scholar
  2. 2.
    Morgensztern D, Ng SH, Gao F, Govindan R (2010) Trends in stage distribution for patients with non-small cell lung cancer: a National Cancer Database survey. J Thorac Oncol 5(1):29–33CrossRefPubMedGoogle Scholar
  3. 3.
    Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C et al (2018) Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol 29(Suppl 4):iv192–iv237CrossRefGoogle Scholar
  4. 4.
    Zhan P, Wang J, Lv X, Wang Q, Qiu L, Lin X et al (2009) Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. J Thorac Oncol 4(9):1094–1103CrossRefPubMedGoogle Scholar
  5. 5.
    Alevizakos M, Kaltsas S, Syrigos KN (2013) The VEGF pathway in lung cancer. Cancer Chemother Pharmacol 72(6):1169–1181CrossRefPubMedGoogle Scholar
  6. 6.
    Piperdi B, Merla A, Perez-Soler R (2014) Targeting angiogenesis in squamous non-small cell lung cancer. Drugs 74(4):403–413CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Koukourakis MI, Papazoglou D, Giatromanolaki A, Bougioukas G, Maltezos E, Sivridis E et al (2004) VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer 46(3):293–298CrossRefPubMedGoogle Scholar
  8. 8.
    Stevens A, Soden J, Brenchley PE, Ralph S, Ray DW (2003) Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. Cancer Res 63(4):812–816PubMedGoogle Scholar
  9. 9.
    Glubb DM, Cerri E, Giese A, Zhang W, Mirza O, Thompson EE et al (2011) Novel functional germline variants in the VEGF receptor 2 gene and their effect on gene expression and microvessel density in lung cancer. Clin Cancer Res 17(16):5257–5267CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Maeda A, Nakata M, Yasuda K, Yukawa T, Saisho S, Okita R et al (2013) Influence of vascular endothelial growth factor single nucleotide polymorphisms on non-small cell lung cancer tumor angiogenesis. Oncol Rep 29(1):39–44CrossRefPubMedGoogle Scholar
  11. 11.
    Dong J, Dai J, Shu Y, Pan S, Xu L, Chen W et al (2010) Polymorphisms in EGFR and VEGF contribute to non-small-cell lung cancer survival in a Chinese population. Carcinogenesis 31(6):1080–1086CrossRefPubMedGoogle Scholar
  12. 12.
    de Mello RA, Ferreira M, Soares-Pires F, Costa S, Cunha J, Oliveira P et al (2013) The impact of polymorphic variations in the 5p15, 6p12, 6p21 and 15q25 Loci on the risk and prognosis of portuguese patients with non-small cell lung cancer. PLoS ONE 8(9):e72373CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Masago K, Fujita S, Kim YH, Hatachi Y, Fukuhara A, Nagai H et al (2009) Effect of vascular endothelial growth factor polymorphisms on survival in advanced-stage non-small-cell lung cancer. Cancer Sci 100(10):1917–1922CrossRefPubMedGoogle Scholar
  14. 14.
    Chen N, Ma CN, Zhao M, Zhang YJ (2015) Role of VEGF gene polymorphisms in the clinical outcome of non-small cell lung cancer. Genet Mol Res 14(4):16006–160011CrossRefPubMedGoogle Scholar
  15. 15.
    Guan X, Yin M, Wei Q, Zhao H, Liu Z, Wang L-E et al (2010) Genotypes and haplotypes of the VEGF gene and survival in locally advanced non-small cell lung cancer patients treated with chemoradiotherapy. BMC Cancer 10:431CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Edge S, Byrd D, Compton C, Fritz A, Greene F, Trotti A (2010) AJCC cancer staging manual. Springer, New YorkGoogle Scholar
  17. 17.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247CrossRefPubMedGoogle Scholar
  18. 18.
    Riera P, Virgili AC, Salazar J, Sebio A, Tobeña M, Sullivan I et al (2018) Genetic variants in the VEGF pathway as prognostic factors in stages II and III colon cancer. Pharmacogenomics J 18(4):556–564CrossRefPubMedGoogle Scholar
  19. 19.
    Sullivan I, Salazar J, Arqueros C, Andrés M, Sebio A, Majem M et al (2017) KRAS genetic variant as a prognostic factor for recurrence in resectable non-small cell lung cancer. Clin Transl Oncol 19(7):884–890CrossRefPubMedGoogle Scholar
  20. 20.
    Glubb DM, Paré-Brunet L, Jantus-Lewintre E, Jiang C, Crona D, Etheridge AS et al (2015) Functional FLT1 genetic variation is a prognostic factor for recurrence in stage I–III non-small-cell lung cancer. J Thorac Oncol 10(7):1067–1075CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Paré-Brunet L, Sebio A, Salazar J, Berenguer-Llergo A, Río E, Barnadas A et al (2015) Genetic variations in the VEGF pathway as prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy. Pharmacogenomics J 15(5):397–404CrossRefPubMedGoogle Scholar
  22. 22.
    Genomes Project Consortium RA, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM et al (2015) A global reference for human genetic variation. Nature 526(7571):68–74CrossRefGoogle Scholar
  23. 23.
    Butkiewicz D, Krześniak M, Drosik A, Giglok M, Gdowicz-Kłosok A, Kosarewicz A et al (2015) The VEGFR2, COX-2 and MMP-2 polymorphisms are associated with clinical outcome of patients with inoperable non-small cell lung cancer. Int J Cancer 137(10):2332–2342CrossRefPubMedGoogle Scholar
  24. 24.
    Uzunoglu FG, Kaufmann C, Wikman H, Güngör C, Bohn BA, Nentwich MF et al (2012) Vascular endothelial growth factor receptor 2 gene polymorphisms as predictors for tumor recurrence and overall survival in non-small-cell lung cancer. Ann Surg Oncol 19(7):2159–2168CrossRefPubMedGoogle Scholar
  25. 25.
    Heist RS, Zhai R, Liu G, Zhou W, Lin X, Su L et al (2008) VEGF polymorphisms and survival in early-stage non-small-cell lung cancer. J Clin Oncol 26(6):856–862CrossRefPubMedGoogle Scholar
  26. 26.
    Eng L, Azad AK, Habbous S, Pang V, Xu W, Maitland-van der Zee AH et al (2012) Vascular endothelial growth factor pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: a systematic review and meta-analysis. Clin Cancer Res 18(17):4526–4537CrossRefPubMedGoogle Scholar
  27. 27.
    Eng L, Liu G (2013) VEGF pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: a 2013 update. Pharmacogenomics 14(13):1659–1667CrossRefPubMedGoogle Scholar
  28. 28.
    Pallaud C, Reck M, Juhasz E, Szima B, Yu C-J, Burdaeva O et al (2014) Clinical genotyping and efficacy outcomes: exploratory biomarker data from the phase II ABIGAIL study of first-line bevacizumab plus chemotherapy in non-squamous non-small-cell lung cancer. Lung Cancer 86(1):67–72CrossRefPubMedGoogle Scholar
  29. 29.
    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):1232–1235CrossRefPubMedGoogle Scholar
  30. 30.
    Yi M, Tang Y, Liu B, Li Q, Zhou X, Yu S et al (2016) Genetic variants in the ITGB6 gene is associated with the risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy. Tumour Biol 37(3):3469–3477CrossRefPubMedGoogle Scholar
  31. 31.
    Paré-Brunet L, Glubb D, Evans P, Berenguer-Llergo A, Etheridge AS, Skol AD et al (2014) Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway. Hum Mutat 35(2):227–235CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Medical Oncology DepartmentHospital de la Santa Creu i Sant PauBarcelonaSpain
  2. 2.Genetics DepartmentHospital de la Santa Creu i Sant PauBarcelonaSpain
  3. 3.Pharmacy DepartmentHospital de la Santa Creu i Sant PauBarcelonaSpain
  4. 4.Faculty of Pharmacy and Food SciencesUniversitat de Barcelona (UB)BarcelonaSpain
  5. 5.Hematology DepartmentManresaSpain
  6. 6.Medical Oncology DepartmentConsorci Sanitari de Terrassa, Carretera de TorrebonicaTerrassaSpain
  7. 7.Medical Oncology DepartmentHospital de Sant Pau i Santa TeclaTarragonaSpain
  8. 8.Medicine DepartmentUniversitat Autònoma de Barcelona (UAB)Bellaterra (Cerdanyola del Vallès)Spain
  9. 9.CIBERER U-705, Hospital de la Santa Creu i Sant PauBarcelonaSpain

Personalised recommendations