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KRAS genetic variant as a prognostic factor for recurrence in resectable non-small cell lung cancer

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Abstract

Purpose

Several angiogenic prognostic markers are under investigation because of their potential clinical utility, aiming to improve patient outcomes. We hypothesized that genetic variant in the VEGF pathway could be used as prognostic markers of survival in non-small cell lung cancer (NSCLC) patients undergoing pulmonary resection.

Methods

We evaluated the relationship between genetic variants in the VEGF pathway and relapse-free survival (RFS, main endpoint) and overall survival (OS, secondary endpoint) among 131 patients with stage I–III NSCLC treated with surgical resection from 2009 to 2013. Clinical, pathological and surgical data were prospectively collected. Twenty-five variants in sixteen relevant genes were selected and genotyped in tumor samples by real time PCR. The Kaplan–Meier method with the log-rank test and Cox’s regression models were used for RFS and OS analyses.

Results

With a median follow-up of 36 (min = 2.8; max = 67.4) months, there were 31 (24%) relapses and 31 (24%) deaths. Overall, median RFS was not reached and median OS was 65 [95% confidence interval (CI) 56–75] months. The KRAS rs1137282 and PIK3C2A rs4356203 variants were significantly associated with RFS. For KRAS rs1137282, the 3-year RFS was 76% [95% CI 64–84%] in patients harboring an A/A genotype compared to 53% [95% CI 37–69%] in patients harboring an A/G or G/G genotype (p = 0.02). For PIK3C2A rs4356203, patients with an A/A or an A/G genotype had a 3-year RFS of 72% [95% CI 58–76%], whereas in patients with a G/G genotype was 49% [95% CI 28–70%] (p = 0.02). These associations remained statistically significant after adjusting for all the relevant clinical parameters in the multivariable analysis.

Conclusion

Genetic variants in VEGF pathway may be associated with recurrence in stage I–III NSCLC. Specifically, the KRAS rs1137282 could be considered as a prognostic factor for recurrence in resectable NSCLC patients. Although PIK3C2A rs4356203 was associated with RFS, further analyses are necessary to confirm these data.

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References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.

    Article  CAS  PubMed  Google Scholar 

  2. Chansky K, Sculier J-P, Crowley JJ, Giroux D, Van Meerbeeck J, Goldstraw P, et al. The international association for the study of lung cancer staging project: prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer. J Thorac Oncol. 2009;4:792–801.

    Article  PubMed  Google Scholar 

  3. Visbal AL, Leighl NB, Feld R, Shepherd FA. Adjuvant chemotherapy for early-stage non-small cell lung cancer. Chest. 2005;128:2933–43.

    Article  CAS  PubMed  Google Scholar 

  4. Burdett S, Pignon JP, Tierney J, Tribodet H, Stewart L, Le Pechoux C, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev. 2015. doi:10.1002/14651858.CD011430.

    PubMed  Google Scholar 

  5. Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267:10931–4.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  9. Stefanou D, Goussia AC, Arkoumani E, Agnantis NJ. Expression of vascular endothelial growth factor and the adhesion molecule E-cadherin in non-small cell lung cancer. Anticancer Res. 2003;23:4715–20.

    CAS  PubMed  Google Scholar 

  10. Zhan P, Wang J, Lv X, Wang Q, Qiu L, Lin X, et al. Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. J Thorac Oncol. 2009;4:1094–103.

    Article  PubMed  Google Scholar 

  11. FDA. Approves new combination therapy for lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108766.htm. Accessed 12 Oct 2006.

  12. European Medicines Agency-Find medicine-Avastin. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000582/human_med_000663.jsp&mid=WC0b01ac058001d124. Accessed 24 Aug 2007.

  13. European Medicines Agency-Find medicine-Vargatef. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002569/human_med_001822.jsp&mid=WC0b01ac058001d124. Accessed 21 Nov 2014.

  14. Guyot M, Pagès G. VEGF splicing and the role of VEGF splice variants: from physiological-pathological conditions to specific pre-mRNA splicing. Methods Mol Biol Clifton NJ. 2015;1332:3–23.

    Article  Google Scholar 

  15. 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  CAS  PubMed  Google Scholar 

  16. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21:154–65.

    Article  CAS  PubMed  Google Scholar 

  17. Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2012;2:a006502.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Jain L, Vargo CA, Danesi R, Sissung TM, Price DK, Venzon D, et al. The role of vascular endothelial growth factor SNPs as predictive and prognostic markers for major solid tumors. Mol Cancer Ther. 2009;8:2496–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Maeda A, Nakata M, Yasuda K, Yukawa T, Saisho S, Okita R, et al. Influence of vascular endothelial growth factor single nucleotide polymorphisms on non-small cell lung cancer tumor angiogenesis. Oncol Rep. 2013;29:39–44.

    CAS  PubMed  Google Scholar 

  20. Koukourakis MI, Papazoglou D, Giatromanolaki A, Bougioukas G, Maltezos E, Sivridis E, et al. VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer. 2004;46:293–8.

    Article  PubMed  Google Scholar 

  21. Stevens A, Soden J, Brenchley PE, Ralph S, Ray DW. Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. Cancer Res. 2003;63:812–6.

    CAS  PubMed  Google Scholar 

  22. 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  CAS  PubMed  PubMed Central  Google Scholar 

  23. Masago K, Fujita S, Kim YH, Hatachi Y, Fukuhara A, Nagai H, et al. Effect of vascular endothelial growth factor polymorphisms on survival in advanced-stage non-small-cell lung cancer. Cancer Sci. 2009;100:1917–22.

    Article  CAS  PubMed  Google Scholar 

  24. Guan X, Yin M, Wei Q, Zhao H, Liu Z, Wang L-E, et al. Genotypes and haplotypes of the VEGF gene and survival in locally advanced non-small cell lung cancer patients treated with chemoradiotherapy. BMC Cancer. 2010;10:431.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yu W, Jiang X, Bai T, Lv X, Chang F. Association between +936 C > T gene polymorphism of vascular endothelial growth factor and lung cancer: a meta-analysis. Cancer Biomark. 2014;14:483–92.

    Article  CAS  PubMed  Google Scholar 

  26. de Mello RA, Ferreira M, Soares-Pires F, Costa S, Cunha J, Oliveira P, et al. 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. 2013;8:e72373.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Heist RS, Zhai R, Liu G, Zhou W, Lin X, Su L, et al. VEGF polymorphisms and survival in early-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:856–62.

    Article  CAS  PubMed  Google Scholar 

  28. Edge SB. In: American Joint Committee on Cancer, editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.

  29. 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  Google Scholar 

  30. FastSNP. http://bioinformatics.ca/links_directory/tool/10250/fastsnp.

  31. SNP Function Prediction (FuncPred). https://snpinfo.niehs.nih.gov/snpinfo/snpfunc.php.

  32. 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. Pharmacogenet Genom. 2013;23:142–7.

    Article  CAS  Google Scholar 

  33. Loupakis F, Ruzzo A, Salvatore L, Cremolini C, Masi G, Frumento P, et al. Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer. BMC Cancer. 2011;11:247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Glubb DM, Cerri E, Giese A, Zhang W, Mirza O, Thompson EE, et al. 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. 2011;17:5257–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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  CAS  PubMed  Google Scholar 

  36. 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  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996;17:343–6.

    Article  CAS  PubMed  Google Scholar 

  38. Dong J, Dai J, Shu Y, Pan S, Xu L, Chen W, et al. Polymorphisms in EGFR and VEGF contribute to non-small-cell lung cancer survival in a Chinese population. Carcinogenesis. 2010;31:1080–6.

    Article  CAS  PubMed  Google Scholar 

  39. Eng L, Azad AK, Habbous S, Pang V, Xu W, Maitland-van der Zee AH, et al. Vascular endothelial growth factor pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: a systematic review and meta-analysis. Clin Cancer Res. 2012;18:4526–37.

    Article  CAS  PubMed  Google Scholar 

  40. Eng L, Liu G. VEGF pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: a 2013 update. Pharmacogenomics. 2013;14:1659–67.

    Article  CAS  PubMed  Google Scholar 

  41. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–9.

    CAS  PubMed  Google Scholar 

  42. Vojtek AB, Der CJ. Increasing complexity of the Ras signaling pathway. J Biol Chem. 1998;273:19925–8.

    Article  CAS  PubMed  Google Scholar 

  43. Rodenhuis S, van de Wetering ML, Mooi WJ, Evers SG, van Zandwijk N, Bos JL. Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med. 1987;317:929–35.

    Article  CAS  PubMed  Google Scholar 

  44. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72:2457–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shepherd FA, Domerg C, Hainaut P, Jänne PA, Pignon J-P, Graziano S, et al. Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol. 2013;31:2173–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wood K, Hensing T, Malik R, Salgia R. Prognostic and predictive value in KRAS in non-small-cell lung cancer: a review. JAMA Oncol. 2016;2:805–12.

    Article  PubMed  Google Scholar 

  47. Wang W-Y, Chien Y-C, Wong Y-K, Lin Y-L, Lin J-C. Effects of KRAS mutation and polymorphism on the risk and prognosis of oral squamous cell carcinoma. Head Neck. 2012;34:663–6.

    Article  PubMed  Google Scholar 

  48. Yuan P, Liu D, Deng M, Liu J, Wang J, Zhang L, et al. Identification of differently expressed genes with specific SNP loci for breast cancer by the integration of SNP and gene expression profiling analyses. Pathol Oncol Res. 2015;21:469–75.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Ivana Sullivan has a Rio Hortega contract (CM13/00117) from the Instituto de Salud Carlos III. Madrid, Spain. This work was performed within the framework of the Doctorate of Medicine at the Autonomous University of Barcelona. The authors thank Carolyn Newey for English language editing.

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    Authors and Affiliations

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

      I. Sullivan, C. Arqueros, M. Andrés, A. Sebio, M. Majem, D. Páez, A. López-Pousa & A. Barnadas

    2. Genetics Department, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, 08025, Barcelona, Spain

      J. Salazar & M. Baiget

    3. CIBERER U-705, Barcelona, Spain

      J. Salazar & M. Baiget

    4. Pathology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

      J. Szafranska

    5. Thoracic Surgery Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

      E. Martínez

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

      I. Sullivan & A. Barnadas

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    1. I. Sullivan
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    All procedures performed in this study were in accordance with the ethical standards of the institutional ethics committee and with the 1964 Helsinki declaration and its later amendments.

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    I. Sullivan and J. Salazar contributed equally to this study.

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    Sullivan, I., Salazar, J., Arqueros, C. et al. KRAS genetic variant as a prognostic factor for recurrence in resectable non-small cell lung cancer. Clin Transl Oncol 19, 884–890 (2017). https://doi.org/10.1007/s12094-017-1620-7

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