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Genetic variants in the VEGF pathway as prognostic factors in stages II and III colon cancer

The Pharmacogenomics Journal volume 18, pages 556–564 (2018)Cite this article

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Abstract

The role of vascular endothelial growth factor (VEGF) gene polymorphisms in the prognosis of colon cancer prognosis remains unclear. We evaluated the influence of 28 single-nucleotide polymorphisms in 12 genes in the VEGF pathway on the prognosis of 347 patients with stage II–III colon cancer. We found that rs9513070 (VEGFR1) and rs1137282 (KRAS) were associated with overall survival in stage II colon cancer patients (p = 0.025 and p = 0.001, respectively). When primary tumor location was considered, rs9513070 was also associated with relapse-free and overall survival (p = 0.033 and p = 0.031, respectively) in left colon cancer patients. Additionally, rs35251833 in the ITGAV gene correlated with relapse-free survival (p = 0.032). This study provides evidence that germline polymorphisms in VEGFR1, KRAS and ITGAV genes are associated with prognosis in stages II–III colon cancer patients. As stage and tumor location are correlated with prognosis, future genetic studies should stratify colon cancer patients according to these parameters.

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References

  1. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics. CA Cancer J Clin. 2014;64:104–17.

    Article  PubMed  Google Scholar 

  2. Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol. 2011;29:1261–70.

    Article  PubMed  Google Scholar 

  3. Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. J Clin Oncol. 2015;33:1787–96.

    Article  PubMed  CAS  Google Scholar 

  4. Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, et al. CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med. 2016;374:211–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Lurje G, Zhang W, Schultheis AM, Yang D, Groshen S, Hendifar AE, et al. Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer. Ann Oncol. 2008;19: 1734–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.

    Article  PubMed  CAS  Google Scholar 

  7. Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9:653–60.

    Article  PubMed  CAS  Google Scholar 

  8. Páez D, Labonte MJ, Bohanes P, Zhang W, Benhanim L, Ning Y, et al. Cancer dormancy: a model of early dissemination and late cancer recurrence. Clin Cancer Res. 2012;18:645–53.

    Article  PubMed  Google Scholar 

  9. Olsson A-K, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol. 2006;7:359–71.

    Article  PubMed  CAS  Google Scholar 

  10. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27.

    Article  PubMed  CAS  Google Scholar 

  11. Maitland ML, Lou XJ, Ramirez J, Desai AA, Berlin DS, McLeod HL, et al. Vascular endothelial growth factor pathway. Pharm Genom. 2010;20:346–9.

    Article  CAS  Google Scholar 

  12. Paré-Brunet L, Glubb D, Evans P, Berenguer-Llergo A, Etheridge AS, Skol AD, et al. Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway. Hum Mutat. 2014;35:227–35.

    Article  PubMed  CAS  Google Scholar 

  13. Gerger A, El-Khoueiry A, Zhang W, Yang D, Singh H, Bohanes P, et al. Pharmacogenetic angiogenesis profiling for first-line Bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Clin Cancer Res. 2011;17:5783–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Paré-Brunet L, Sebio A, Salazar J, Berenguer-Llergo A, Río E, Barnadas A, et al. Genetic variations in the VEGF pathway as prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy. Pharm J. 2015;15:397–404.

    Google Scholar 

  15. Sebio A, Paré L, Páez D, Salazar J, González A, Sala N, et al. The LCS6 polymorphism in the binding site of let-7 microRNA to the KRAS 3’-untranslated region: its role in the efficacy of anti-EGFR-based therapy in metastatic colorectal cancer patients. Pharm Genom. 2013;23:142–7.

    Article  CAS  Google Scholar 

  16. Glubb DM, Paré-Brunet L, Jantus-Lewintre E, Jiang C, Crona D, Etheridge AS, et al. Functional FLT1 genetic variation is a prognostic factor for recurrence in stage I–III non-small-cell lung cancer. J Thorac Oncol. 2015;10:1067–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Sullivan I, Salazar J, Arqueros C, Andrés M, Sebio A, Majem M, et al. KRAS genetic variant as a prognostic factor for recurrence in resectable non-small cell lung cancer. Clin Transl Oncol. 2017;19:884–90.

    Article  PubMed  CAS  Google Scholar 

  18. Rollin J, Payancé A, Gouilleux-Gruart V, Boisdron-Celle M, Azzopardi N, Morel A, et al. Significant effect of VEGFA polymorphisms on the clinical outcome of metastatic colorectal cancer patients treated with FOLFIRI-cetuximab. Pharmacogenomics. 2015;16:2035–43.

    Article  PubMed  CAS  Google Scholar 

  19. Dassoulas K, Gazouli M, Rizos S, Theodoropoulos G, Christoni Z, Nikiteas N, et al. Common polymorphisms in the vascular endothelial growth factor gene and colorectal cancer development, prognosis, and survival. Mol Carcinog. 2009;48:563–9.

    Article  PubMed  CAS  Google Scholar 

  20. Pallaud C, Reck M, Juhasz E, Szima B, Yu C-J, Burdaeva O, et al. 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. 2014;86:67–72.

    Article  PubMed  Google Scholar 

  21. Sohn BS, Park SJ, Kim JE, Kim K-P, Hong YS, Suh C, et al. Single-nucleotide polymorphisms in the vascular endothelial growth factor pathway and outcomes of patients treated with first-line cytotoxic chemotherapy combined with bevacizumab for advanced colorectal cancer. Oncology. 2014;87:280–92.

    Article  PubMed  CAS  Google Scholar 

  22. Dong G, Guo X, Fu X, Wan S, Zhou F, Myers RE, et al. Potentially functional genetic variants in KDR gene as prognostic markers in patients with resected colorectal cancer. Cancer Sci. 2012;103:561–8.

    Article  PubMed  CAS  Google Scholar 

  23. Lurje G, Hendifar AE, Schultheis AM, Pohl A, Husain H, Yang D, et al. Polymorphisms in interleukin 1 beta and interleukin 1 receptor antagonist associated with tumor recurrence in stage II colon cancer. Pharm Genom. 2009;19:95–102.

    Article  CAS  Google Scholar 

  24. Kjaer-Frifeldt S, Fredslund R, Lindebjerg J, Hansen TF, Spindler K-LG, Jakobsen A, et al. Prognostic importance of VEGF-A haplotype combinations in a stage II colon cancer population. Pharmacogenomics. 2012;13:763–70.

    Article  PubMed  CAS  Google Scholar 

  25. Shen H, Yang J, Huang Q, Jiang M-J, Tan Y-N, Fu J-F, et al. Different treatment strategies and molecular features between right-sided and left-sided colon cancers. World J Gastroenterol. 2015;21:6470.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Lee MS, Menter DG, Kopetz S. Right versus left colon cancer biology: integrating the consensus molecular subtypes. J Natl Compr Canc Netw. 2017;15:411–9.

    Article  PubMed  Google Scholar 

  27. Sinicrope FA, Mahoney MR, Yoon HH, Smyrk TC, Thibodeau SN, Goldberg RM, et al. Analysis of molecular markers by anatomic tumor site in stage III colon carcinomas from adjuvant chemotherapy trial NCCTG N0147 (Alliance). Clin Cancer Res. 2015;21:5294–304.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Sinicrope FA, Mahoney MR, Smyrk TC, Thibodeau SN, Warren RS, Bertagnolli MM, et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol. 2013;31:3664–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Sinicrope FA, Shi Q, Allegra CJ, Smyrk TC, Thibodeau SN, Goldberg RM, et al. Association of DNA mismatch repair and mutations in BRAF and KRAS with survival after recurrence in stage III colon cancers. JAMA Oncol. 2017;3:472.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ulivi P, Scarpi E, Chiadini E, Marisi G, Valgiusti M, Capelli L, et al. Right- vs. left-sided metastatic colorectal cancer: differences in tumor biology and Bevacizumab efficacy.Int J Mol Sci. 2017;18:1240

    Article  PubMed Central  Google Scholar 

  31. Ning Y, Lurje G, Danenberg K, Cooc J, Yang D, Pohl A, et al. VEGF and VEGFR1 gene expression levels and tumor recurrence in adjuvant colon cancer. J Clin Oncol. 2009;27 Suppl 15:4040.

  32. Bohanes P, Yang D, Loupakis F, LaBonte MJ, Gerger A, Ning Y, et al. Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer. Pharm J. 2015;15: 226–34.

    CAS  Google Scholar 

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Acknowledgements

This work was supported by the Departament d’Economia i Coneixement de la Generalitat de Catalunya (2016FI_B 00368 to Pau Riera).

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    Authors and Affiliations

    1. Genetics Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

      Pau Riera & Juliana Salazar

    2. Universitat de Barcelona (UB), Barcelona, Spain

      Pau Riera

    3. Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

      Anna C. Virgili, Ana Sebio, María Tobeña, Ivana Sullivan & David Páez

    4. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

      Anna C. Virgili

    5. CIBERER, U-705, Barcelona, Spain

      Juliana Salazar

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    Pau Riera and Anna C. Virgili contributed equally to this study.

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    Riera, P., Virgili, A.C., Salazar, J. et al. Genetic variants in the VEGF pathway as prognostic factors in stages II and III colon cancer. Pharmacogenomics J 18, 556–564 (2018). https://doi.org/10.1038/s41397-017-0009-x

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