Vascular endothelial growth factor gene polymorphisms and ovarian cancer survival
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
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