Annals of Surgical Oncology

, Volume 21, Issue 2, pp 612–620

A Gene Signature Combining the Tissue Expression of Three Angiogenic Factors is a Prognostic Marker in Early-stage Non-small Cell Lung Cancer

  • Elena Sanmartín
  • Rafael Sirera
  • Marta Usó
  • Ana Blasco
  • Sandra Gallach
  • Santiago Figueroa
  • Nieves Martínez
  • Cristina Hernando
  • Antonio Honguero
  • Miguel Martorell
  • Ricardo Guijarro
  • Rafael Rosell
  • Eloisa Jantus-Lewintre
  • Carlos Camps
Thoracic Oncology

DOI: 10.1245/s10434-013-3330-x

Cite this article as:
Sanmartín, E., Sirera, R., Usó, M. et al. Ann Surg Oncol (2014) 21: 612. doi:10.1245/s10434-013-3330-x

Abstract

Background

Angiogenesis and lymphangiogenesis are key mechanisms for tumor growth and dissemination. They are mainly regulated by the vascular endothelial growth factor (VEGF) family of ligands and receptors. The aim of this study was to analyze relative expression levels of angiogenic markers in resectable non-small cell lung cancer patients in order to asses a prognostic signature that could improve characterization of patients with worse clinical outcomes.

Methods

RNA was obtained from tumor and normal lung specimens from 175 patients. Quantitative polymerase chain reaction was performed to analyze the relative expression of HIF1A, PlGF, VEGFA, VEGFA165b, VEGFB, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, NRP1 and NRP2.

Results

Univariate analysis showed that tumor size and ECOG-PS are prognostic factors for time to progression (TTP) and overall survival (OS). This analysis in the case of angiogenic factors also revealed that PlGF, VEGFA, VEGFB and VEGFD distinguish patients with different outcomes. Taking into account the complex interplay between the different ligands of the VEGF family and to more precisely predict the outcome of the patients, we considered a new analysis combining several VEGF ligands. In order to find independent prognostic variables, we performed a multivariate Cox analysis, which showed that the subgroup of patients with higher relative expression of VEGFA plus lower VEGFB and VEGFD presented the poorest outcome for both TTP and OS.

Conclusions

The relative expression of these three genes can be considered as an angiogenic gene signature whose applicability for the selection of candidates for targeted therapies needs to be further validated.

Supplementary material

10434_2013_3330_MOESM1_ESM.doc (47 kb)
Supplementary Table I. Patient characteristics according to the levels of the combined variables VEGFA, VEGFB and VEGFD. ap was calculated by Mann–Whitney test in the case of age and Chi square test in the case of the others non-continuous variables. Abbreviations: ADC, adenocarcinomas; SCC, squamous cell carcinomas; ↑, high expression; ↓, low expression (DOC 47 kb)
10434_2013_3330_MOESM2_ESM.ai (184 kb)
Supplementary Figure 1. Kaplan–Meier plots according to coexpression of VEGFA, VEGFB and VEGFD for TTP and OS in (A) postoperative treated patients and (B) no postoperative treated patients. Legend for Supplementary Figure 1. Abbreviations: VEGF, vascular endothelial growth factor; TTP, time to progression; OS, overall survival. (AI 184 kb)

Copyright information

© Society of Surgical Oncology 2013

Authors and Affiliations

  • Elena Sanmartín
    • 1
  • Rafael Sirera
    • 2
  • Marta Usó
    • 1
  • Ana Blasco
    • 3
  • Sandra Gallach
    • 1
  • Santiago Figueroa
    • 4
  • Nieves Martínez
    • 3
  • Cristina Hernando
    • 3
  • Antonio Honguero
    • 5
  • Miguel Martorell
    • 6
  • Ricardo Guijarro
    • 4
  • Rafael Rosell
    • 7
  • Eloisa Jantus-Lewintre
    • 1
  • Carlos Camps
    • 1
    • 3
    • 8
  1. 1.Molecular Oncology Laboratory, Fundación InvestigaciónHospital General Universitario de ValenciaValenciaSpain
  2. 2.Department of BiotechnologyUniversitat Politècnica de ValènciaValenciaSpain
  3. 3.Medical Oncology DepartmentHospital General Universitario de ValenciaValenciaSpain
  4. 4.Department of Thoracic SurgeryHospital General Universitario de ValenciaValenciaSpain
  5. 5.Department of Thoracic SurgeryHospital General Universitario de AlbaceteAlbaceteSpain
  6. 6.Department of PathologyHospital General Universitario de ValenciaValenciaSpain
  7. 7.Medical Oncology Department, Catalan Institute of OncologyHospital Germans Trias i PujolBadalonaSpain
  8. 8.Department of MedicineUniversitat de ValenciaValenciaSpain