Elsevier

Gynecologic Oncology

Volume 119, Issue 3, December 2010, Pages 479-483
Gynecologic Oncology

Vascular endothelial growth factor gene polymorphisms and ovarian cancer survival

https://doi.org/10.1016/j.ygyno.2010.08.014Get rights and content

Abstract

Objectives

We sought to evaluate the effect of polymorphisms in the VEGF (Vascular Endothelial Growth Factor) gene on overall survival in ovarian cancer patients.

Methods

A sample of 319 women diagnosed with primary invasive epithelial ovarian cancer in Australia between 1985 and 1997, recruited as incident cases, were genotyped for four VEGF single nucleotide polymorphisms (three tagSNPs and one functional SNP) using the Sequenom MassARRAY platform. A SNP found to be associated with ovarian cancer survival in this sample set was then evaluated in two independent datasets in an attempt to replicate the association.

Results

VEGF tagSNPs rs3025033 and rs2146323 were not associated with ovarian cancer survival in the Australian sample. Ovarian cancer patients homozygous for tagSNP rs833068 or the functional SNP rs2010963 displayed significantly shortened overall survival in the Australian sample (HR 2.09, 95% CI 1.16–3.78), an effect most apparent in the first 5 years after diagnosis. This association was not replicated in two independent datasets.

Conclusions

Findings from this study provide no evidence that rs3025033 and rs2146323 VEGF polymorphisms are associated with ovarian cancer survival. Although homozygous carriers of the tagSNP rs833068 experienced significantly worse survival in our Australian dataset, we were unable to replicate this in two independent datasets.

Introduction

It is well known that tumor growth is critically dependent upon the development of new blood vessels, or angiogenesis [1]. Early in tumorigenesis there is upregulation of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and downregulation of important negative angiogenic regulators. VEGF levels are elevated in malignant ovarian tumors [2], [3] and, in combination with three other proteins (including CA125), VEGF expression was able to classify 100% of ovarian cancers in a study of 158 ovarian cancers of various histotypes [4]. Numerous studies have reported high VEGF levels in ovarian cancer patients associated with advanced tumor stage [3], [5], [6], metastasis [3], poor disease-free survival [7] and shortened overall survival [6], [7], [8], [9], [10]. Due to its important role in cancer, many agents have been developed to target either the VEGF ligand or receptor. Bevacizumab is a monoclonal antibody that targets the VEGF ligand and has demonstrated activity in ovarian cancer patients [1].

The VEGF gene, which is located at 6p21.1, consists of eight exons and lies within three main blocks of linkage disequilibrium (LD) [11]. Several common VEGF single nucleotide polymorphisms (SNPs) such as rs2010963G > C (also known as + 405G > C or −634G > C), rs699947A > C (−2578A > C), and rs1570360G > A (−1154G > A) have been shown to directly alter or be associated with VEGF expression levels [12], [13], [14], [15], [16], [17], [18]. Specifically, the rs2010963G > C SNP, located in the 5' untranslated region of VEGF, has been shown to affect VEGF expression in vitro, with the CC genotype increasing VEGF production over the wildtype GG genotype [15], [16], [18]. Lambrechts et al. [15] further clarified this finding and identified that a specific VEGF isoform, Long-VEGF (L-VEGF), was overexpressed in the presence of this SNP, resulting in an increase in overall VEGF levels. The L-VEGF isoform is 180 amino acids longer than the common form of VEGF and although its function has not been elucidated, L-VEGF has been shown to be overexpressed in tumors, similar to VEGF [19]. However, there have been mixed reports regarding rs2010963G > C and VEGF expression in vivo, with several studies describing altered levels of VEGF [15], [17] and others reporting no effect [20], [21], [22], [23].

VEGF polymorphisms have been the focus of investigation for a role in cancer predisposition and prognosis in recent years, including cancers of the breast [24], [25], prostate [23], [26], colorectum [27] and bladder [11]. Recently, two groups have reported specific VEGF polymorphisms and haplotypes associated with reduced progression-free survival and overall survival in ovarian cancer patients [13], [28], [29]. We sought to further investigate the role of common variation in the VEGF gene in ovarian cancer prognosis using VEGF tagSNPs rs833068G > A, rs2146323C > A and rs3025033A > G, and the functional polymorphism rs2010963G > C. We also drew on two large datasets in an attempt to replicate findings for a SNP found to be associated with survival in the Australian sample set.

Section snippets

Study participants

This study included 319 women diagnosed with primary invasive epithelial ovarian cancer between 1985 and 1997. Over half of the women (n = 207 [65%]) had participated in a large population-based case-control study of the etiology of ovarian cancer. The mean time from date of diagnosis to date of interview in this group of women was 58 days. The remaining women (n = 112 [35%]) were ascertained as incident cases from the Royal Brisbane Hospital, Queensland, Australia. The study was approved by the

Results

Among the 319 Australian women with ovarian cancer, 188 (59%) died from the disease during the follow-up period, giving a 5-year survival proportion of 45%. Selected clinical and pathologic characteristics of the Australian women and the women in the two independent datasets, the UK GWAS and TCGA, are shown in Table 1. Among the Australian women a little over three quarters were older than ≥ 50 years at diagnosis (77%), and many presented with late stage disease (71%) and high grade tumors (54%).

Discussion

Several studies have reported that polymorphisms in the VEGF gene are associated with a number of different characteristics of cancer, including susceptibility [36], tumor grade [23], [36], [37] and overall survival [27], [38]. In ovarian cancer the VEGF haplotype rs699947A/ rs1570360G/ rs833061C/ rs2010963G/ rs3025039C has recently been reported to be associated with decreased serum levels of VEGF and improved progression-free survival [13]. Furthermore, the VEGF rs3025039C allele (also known

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

We thank the patients and control subjects who participated so willingly in our studies. We thank the SEARCH team and the Eastern Cancer Registration and Information Centre. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov. Amanda Spurdle is supported by an

References (38)

  • S. Sfar et al.

    Association of VEGF genetic polymorphisms with prostate carcinoma risk and clinical outcome

    Cytokine

    (2006)
  • G.C. Kumaran et al.

    Antiangiogenic drugs in ovarian cancer

    Br J Cancer

    (2009)
  • L. Li et al.

    Correlation of serum VEGF levels with clinical stage, therapy efficacy, tumor metastasis and patient survival in ovarian cancer

    Anticancer Res

    (2004)
  • K.H. Lu et al.

    Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis

    Clin Cancer Res

    (2004)
  • C. Rudlowski et al.

    Prognostic significance of vascular endothelial growth factor expression in ovarian cancer patients: a long-term follow-up

    Int J Gynecol Cancer

    (2006)
  • M.J. Goodheart et al.

    The relationship of molecular markers of p53 function and angiogenesis to prognosis of stage I epithelial ovarian cancer

    Clin Cancer Res

    (2005)
  • M. Garcia-Closas et al.

    Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk

    PLoS Genet

    (2007)
  • M. Shahbazi et al.

    Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection

    J Am Soc Nephrol

    (2002)
  • Steffensen KD, Waldstrom M, Brandslund I, Jakobsen A. The relationship of VEGF polymorphisms with serum VEGF levels and...
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