Guan et al. BMC Cancer 2010, 10:431 http://www.biomedcentral.com/1471-2407/10/431 confounding effects of clinical parameters on the asso- ciation, we limited our study subjects to a group of 124 Caucasian patients with homogenous stage IIIa and IIIb NSCLC, who received well-documented definitive che- moradiotherapy as previously described [13]. We found that the VEGF - 460 C variant genotypes were asso- ciated with a significantly improved OS, compared with the VEGF -460 TT genotype. To give a comprehensive view of the association between VEGF genotypes and the prognosis of different cancer types, we summarized the published data in Table 3. Most of these studies confirmed an influence of VEGF SNPs on the overall survival of cancer patients. However, these studies differed substantially in their conclusions. Even for the same VEGF SNP, different risk allele was reported. Different ethnic populations might be one rational reason for the inconsistent results. Another possible explanation may be that the effects of VEGF are tumor-specific. The interaction of different therapeutic strategies with VEGF genotypes may also contribute to the diverse clinical outcomes. In NSCLC, the three studies (including ours) were not consistent in the VEGF risk alleles, suggesting that a further investiga- tion was warranted. For example, Masago et al. reported an association between -460 C allele and a poorer survi- val of advanced NSCLC in Japanese patients [20], which was opposite to our findings in Caucasian patients. Numerous factors could have played a role in the ethnic discrepancy, including gene-gene interaction from differ- ent genetic background and gene-environmental interac- tion from different lifestyles. Even in the same ethnicity Page 7 of 9 of Caucasians, the study by Heist et al. failed to find any significant association between -460 C allele and survival in 462 early-stage NSCLC patients, most of whom were surgically resected [9]. In that study, there were only 32 patients (7%) receiving radiation and three patients (0.6%) treated with chemotherapy. In contrast, the 124 LA-NSCLC patients of current study all received radio- therapy, and carriers of the C allele of -460 T > C poly- morphism were found to benefit from radiotherapy. These findings, once validated in larger studies, will guide tailored therapeutics for individual patients. It is not clear how the VEGF -460 C allele contri- butes to a better survival in LA-NSCLC patients. A previous in vitro study indicated that the T allele of the VEGF -460 T > C polymorphism located in the promoter of the VEGF gene was associated with a decreased VEGF promoter activity [10]. Hence, the VEGF -460 C allele may be associated with an increased VEGF expression, which would promote tumor angiogenesis. However, the majority of NSCLC patients included in the current study received che- motherapy in addition to radiotherapy (112 out of 124). It is possible that the increased tumor vascula- ture may enhance radiotherapy efficacy through inhi- biting tumor radioresistance from radiation-induced hypoxia, or facilitate the delivery of chemotherapeutic agents to the tumor site and may have led to enhanced synergistic effect with radiotherapy. Or, the VEGF -460 C allele has some additional unknown biological func- tions, besides regulation of mRNA expression. Further mechanistic studies are required to clarify this issue. Table 3 Summary of the influence of VEGF SNPs on cancer OS First author Year Cancer Country Ethnicity SNPs No. Risk allele Guan 2010 LA-NSCLC USA Caucasian -460T > C, -634G > C, and 936C > T 124 T for -460T > C (Current) Formento 2009 Head&neck France Caucasian -460T > C, -634G > C, and 936C > T 49 None [23] Masago 2009 Advanced Japan Asian -460T > C, -1154G > A, -2578C > A, 126 C for -460T > C, A for -1154G > A, and A for [20] NSCLC 405G > C, and 936C > T -2578C > A Dassoulas 2009 Colorectum Greece Caucasian -460T > C, -634G > C, -1154G > A, 312 T for -460T > C, G for -634G > C, C for -2578C [24] -2578C > A, and 936C > T > A, and C for 936C > T Bradbury 2009 Esophagus Canada Caucasian -460T > C, 405G > C, and 936C > T 361 C for 936C > T [25] Heist [9] 2008 Early USA Caucasian -460T > C, 405G > C, and 936C > T 462 G for 405G > C and C for 936C > T NSCLC Kim [16] 2008 Colorectum Korea Asian -634G > C, -2578C > A, and 936C > T 445 G for -634G > C and T for 936C > T Kim [26] 2007 Stomach Korea Asian -116G > A, -460T > C, 405G > C, and 503 C for -460T > C and T for 936C > T 936C > T Kawai [27] 2007 Renal cell Japan Asian -634G > C, -2578C > A, and -1154G > A 213 C for -2578C > A Hefler [17] 2007 Ovarian Austria Caucasian -634G > C, -1154G > A, and -2578C > A 563 None Tzanakis 2006 Stomach Greece Caucasian -634G > C, -2578C > A, -1154G > A, 100 C for -634G > C [28] and 936C > T Lu [19] 2005 Breast China Asian -460T > C, 405G > C, and 936C > T 1119 C for -460T > C, and G for 405G > C