Skip to main content

Association of VEGF haplotypes with breast cancer risk in North-West Indians

 Abstract

Background

Angiogenesis is a complex and coordinated process regulated by different growth factors and is one of the hallmark features of cancer. VEGF is one of the most important endothelial cell mitogen and has a critical role in normal physiological and tumor angiogenesis. The objective of this study was to investigate the potential association of haplotypes of six VEGF polymorphisms with breast cancer risk in North-West Indians.

Methods

Samples of 250 breast cancer patients and 250 age and sex matched controls were genotyped for VEGF −2578C/A, −2549I/D, −460T/C, +405C/G, −7C/T and +936C/T polymorphisms. Haplotypes were generated to determine the better contribution of VEGF polymorphisms to breast cancer risk.

Results

Haplotypes CDTCCC (OR = 0.56, 95%CI, 0.38–0.81; p = 0.003) and CDTGCC (OR = 0.63, 95%CI, 0.44–0.92; p = 0.018) of VEGF −2578C/A, −2549I/D, −460T/C, +405C/G, −7C/T and +936C/T polymorphisms were significantly associated with decreased risk of breast cancer. CDTCCC haplotype was also significantly associated with reduced risk of breast cancer in pre and post menopausal as well as both obese and non obese patients. Haplotype CDTGCC was marginally associated (p = 0.07) with reduced risk of breast cancer in non-obese patients as compared with non-obese controls where as haplotype AICGTC was marginally associated (p = 0.09) with reduced risk of breast cancer in obese patients when compared with non-obese patients. The CDTGCC haplotype was significantly associated with increased risk of breast cancer in premenopausal obese patients (OR = 1.98, 95%CI, 1.10–3.56; p = 0.02).

Conclusions

Our data indicated that CDTCCC and CDTGCC haplotypes of VEGF −2578C/A, −2549I/D, −460T/C, +405C/G, −7C/T and +936C/T polymorphisms were significantly associated with breast cancer risk in North-West Indians. Further studies on multiethnic groups with larger sample size are required to confirm our results.

Peer Review reports

Background

Angiogenesis is one of the hallmark features of cancer [1]. It is a complex and coordinated process regulated by different growth factors like platelet derived growth factor, transforming growth factor and angiopoietins among which vascular endothelial growth factors (VEGF) play a crucial role [2,3,4]. VEGF is one of the most powerful endothelial cell mitogen and has a very critical role in normal physiological and tumor angiogenesis [5,6,7]. It enhances tumor vessel permeability and endothelial cell proliferation, migration, differentiation, capillary formation and also has proinflammatory actions [8,9,10,11,12].

The VEGFA also known as VEGF is located at 6p21.3 and it comprises eight exons and seven introns (Fig. 1) [13]. It is highly polymorphic with several polymorphisms in the promoter, 5′-untranslated region (5′-UTR) and 3′-UTR [14, 15]. Polymorphisms in the promoter and UTRs have been reported to regulate VEGF expression via alternative initiation of transcription and internal initiation of translation [16, 17]. Functional genetic polymorphisms which alter the regulation of gene expression are predicted to have a significant impact on disease pathogenesis [18]. VEGF −2578C/A, −2549I/D, −460T/C, −116G/A, +405C/G and +936C/T polymorphisms have been associated with differential expression of VEGF [14, 15, 19,20,21,22]. The importance of VEGFA in breast cancer has been described in several studies [23, 24]. Increased expression of VEGF has been documented in invasive and non invasive breast cancer tissue [25, 26]. Polymorphisms in promoter, 5′-UTR and 3′-UTR of VEGF have been reported to affect translation efficiency, circulating plasma concentrations and tumor tissue expression of VEGF [19, 27]. It has been documented that VEGF polymorphisms influencing VEGF expression in normal cells might have an impact on tumorigenesis, tumor progression, and response to anti-VEGF agents [22, 28,29,30].

Fig. 1
figure1

Schematic diagram showing chromosomal position of VEGF and locations of analyzed polymorphisms

Haplotype analysis could be a better predictive approach rather than investigating individual polymorphism. It estimates more specific risk and reduces the dimension of association tests and increase statistical power [31]. Due to the important role of VEGF in carcinogenesis, the present study aimed to investigate the association of haplotypes of VEGF −2578C/A (−1540C/A), −2549I/D (−1511I/D), −460T/C (−1498T/C), +405C/G (−634C/G), −7C/T (+1032C/T) and +936C/T polymorphisms with breast cancer risk in North-West Indians. So far there is no combined report on these six VEGF polymorphisms in breast cancer. To the best of our knowledge, this is the first study evaluating the potential association of haplotypes of VEGF −2578C/A (rs699947), −2549I/D (rs35569394), −460T/C (rs833061), +405C/G (rs2010963) −7C/T (rs25648) and +936C/T (rs3025039) polymorphism with breast cancer risk.

Methods

Subjects

The study was performed according to Declaration of Helsinki and was approved by the Ethics Committee of Guru Nanak Dev University, Amritsar, Punjab, India. All the subjects gave a written informed consent with a signature or thumb impression. A total of 500 subjects (250 breast cancer patients and 250 healthy controls) were analyzed in this study. The patients were investigated at Sri Guru Ram Das Institute of Medical Sciences and Research, Vallah, Amritsar, Punjab (India). The selection criteria of patients and controls have been described in our previous study [32]. All the subjects gave 5 ml blood samples for genetic analyses.

Genotyping of VEGF polymorphisms and analyses of data

The DNA was extracted from EDTA-anti-coagulated blood samples using organic method [33] with few modifications. Three promoter (VEGF −2578C/A, −2549I/D, −460T/C), two 5′-UTR (+405C/G, −7C/T), and one 3´-UTR (+936C/T) polymorphisms were analyzed in this study (Fig. 1). The VEGF −2549I/D polymorphism was analyzed by direct PCR. VEGF −460T/C, −2578C/A +405C/G and VEGF +936C/T polymorphisms of VEGF were analyzed using PCR–RFLP method. VEGF −7C/T polymorphism was analyzed by ARMS-PCR. Ten percent of randomly selected samples were sequenced to validate the PCR based assay genotyping and results of both sets of analyses were 100% concordant. The detail of reaction conditions and analysis of genotype data have been described in our published studies [34, 35]. To determine the better contribution of VEGF polymorphisms to breast cancer risk, haplotypes of six VEGF polymorphisms were generated using the online SNPStats software [36]. Further we predicted the possible influence of studied VEGF polymorphisms on the transcription factor binding sites using online software TFSEARCH (http://www.cbrc.jp/research/db/TFSEARCH.html).

Results

Characteristics of study participants

The demographic characteristics of study participants were presented in Table 1. The mean age of patients was 49.38 ± 11.87 years and of controls was 49.34 ± 11.85 years. Of the 250 breast cancer patients, 234 (93%) had infiltrating ductal carcinoma, 4 (2%) had infiltrating lobular carcinoma and 12 (5%) had other types of cancer like medullary carcinoma, mucinous carcinoma, Paget’s disease and phyllodes tumor. In the present study, 127 (51%) cases had tumor in left breast, 112 (45%) in right breast and 11 (4%) cases had tumor in both breasts. Of the 250 breast cancer patients, 65 (26%) had stage I, 119 (48%) had stage II, 48 (19%) had stage III, and 18 (7%) had stage IV tumor.

Table 1 Characteristics of Breast cancer patients and healthy controls

Association of VEGF polymorphisms with breast cancer

The results of association of individual VEGF polymorphism were summarized (Additional file 1: Table S1). The AA genotype and A allele of VEGF −2578C/A, II genotype and I allele of VEGF −2549I/D, CC genotype and C allele of VEGF −460T/C, GG genotype and G allele of VEGF +405C/G polymorphism was significantly associated with increased risk of breast cancer. No association of VEGF −7C/T and +936C/T polymorphism with breast cancer risk was observed. We analyzed haplotypes of VEGF −2578C/A, −2549I/D, −460T/C, +405C/G, −7C/T and +936C/T polymorphisms to determine if there is any difference in VEGF haplotypes between breast cancer patients and healthy controls. The most common haplotype in the present study was AICGCC, with the frequencies of 31.3% in breast cancer patients and 23.8% in healthy control individuals. We observed that CDTCCC (OR = 0.56, 95%CI, 0.38–0.81; p = 0.003) and CDTGCC (OR = 0.63, 95%CI, 0.44–0.92; p = 0.018) haplotypes were significantly associated with decreased risk of breast cancer (Table 2). CDTCCC haplotype was significantly associated with reduced risk of breast cancer in pre and post menopausal patients (Tables 3 and 4). None of the VEGF haplotype was associated with breast cancer risk in pre menopausal patients when compared with post menopausal patients (Table 5). The CDTCCC haplotype was also significantly associated with decreased risk of breast cancer in both obese and non obese patients (Tables 6 and 7). Haplotype CDTGCC was marginally associated (p = 0.07) with reduced risk of breast cancer in non-obese patients as compared with non-obese controls (Table 7) where as haplotype AICGTC was marginally associated (p = 0.09) with reduced risk of breast cancer in obese patients when compared with non-obese patients (Table 8). Further we compared pre menopausal obese patients with post menopausal obese patients and observed that CDTGCC haplotype was significantly associated (p = 0.02) with increased risk of breast cancer in premenopausal obese patients (Table 9).

Table 2 Association between VEGF haplotypes and breast cancer risk
Table 3 VEGF haplotypes and breast cancer risk in premenopausal subjects
Table 4 VEGF haplotype and breast cancer risk in post menopausal subjects
Table 5 Association of VEGF haplotypes with breast cancer risk in pre menopausal and post menopausal patients
Table 6 Association of VEGF haplotypes with breast cancer risk in obese subjects
Table 7 Association of VEGF haplotypes with breast cancer risk in non obese subjects
Table 8 Association of VEGF haplotypes with breast cancer risk in obese and non obese patients
Table 9 Association of VEGF haplotypes with breast cancer risk in pre menopausal obese and post menopausal obese patients

The TFSEARCH software was used to predict the functional significance of VEGF polymorphisms. Based on the difference in TFSEARCH TFBS scores, VEGF −2578C/A and +405C/G polymorphisms were predicted to alter a transcription factor binding site. VEGF −2578A allele abolish the binding site of GATA-2 transcription factor where as VEGF +405G allele created the binding site of MZF1 (Myeloid zinc finger 1) transcription factor.

Discussion

In the present study we investigated the potential association of VEGF haplotypes based on six polymorphisms with breast cancer risk. In previous reported studies, by using the single/double or triple polymorphism approach, VEGF −2578C/A, −2549I/D, −460T/C, +405C/G, −7C/T and +936C/T polymorphisms have been analyzed to evaluate their potential association with breast cancer risk in different ethnic groups and results are conflicting (Additional file 1: Table S2). The ethnicity difference and inadequate sample size could be the potential cause of inconsistent results.

In the present study, we observed that CDTCCC (OR = 0.56, 95%CI, 0.38–0.81; p = 0.003) and CDTGCC (OR = 0.63, 95%CI, 0.44–0.92; p = 0.018) haplotypes of VEGF −2578C/A, −2549I/D, −460T/C, +405C/G, −7C/T and +936C/T polymorphisms were significantly associated with reduced risk of breast cancer. In none of the previous studies, these six polymorphisms have been reported together. In Caucasian subjects, − 460T/+405C/ − 7C/, +936C haplotype was associated with reduced risk of breast cancer [46]. Significant association of VEGF −2578A/−1154A/+405G haplotype with decreased risk of invasive breast cancer has been reported in American population [44]. Haplotype VEGF −1154A/−2578A/−634G/−460C was associated with decreased risk of breast cancer in Moroccan population [39]. The −2578A/−1154G/+405G haplotype was associated with decreased risk whereas haplotype −2578C/−1154G/+405G was associated with increased risk of breast cancer recurrence in Caucasian women [58]. Association of −2578C/+405C haplotype with tumor size and higher histological grade has been documented in breast cancer patients [45]. None of the haplotype of VEGF −2578C/A, −2549I/D, −460T/C, +405C/G, and +936C/T polymorphisms was associated with breast cancer risk in Iranian population [38].

VEGF −460C/+405G/+936T haplotype was associated with decreased risk of lung cancer in Koreans [59] and increased risk of esophageal adenocarcinoma in Caucasian [60]. The TGC haplotype of VEGF −460C/T, +405C/G and +936C/T polymorphism was significantly associated with decreased risk of adenocarcinoma among male non-small cell lung cancer patients [61]. In Turkish population, VEGF −2578A/+936T/−460T haplotype has been reported to be associated with increased risk of colorectal cancer [62]. In Tunisians, CIC haplotype of VEGF −2578C/A, −2549I/D and +936C/T polymorphisms was associated with increased risk of urothelial bladder cancer [63].

There are some studies from India on different diseases showing association of VEGF haplotypes with disease risk. The CTIG haplotype of VEGF −2578C/A, −7C/T, −2549I/D, and −1001G/C polymorphisms was associated with increased risk of bladder cancer [64] whereas TACI haplotype of VEGF +936C/T, −1154G/A, −2578C/A and −2549I/D polymorphisms was associated with increased risk of end stage renal disease [65]. Haplotypes CGCC and CGGC of VEGF −460T/C, −1154G/A, +405C/G, and +936C/T polymorphism were associated with aggressiveness of disease in epithelial ovarian cancer patients [66]. No association of VEGF +405C/G and +936C/T haplotypes with lung cancer risk has been reported in Kashmiri patients [67].

In the present study, CDTCCC haplotype was significantly associated with reduced risk of breast cancer in pre menopausal as well as in post menopausal patients when compared with pre and post menopausal controls. The breast cancer risk has also been reported to be modulated by menopause [68]. Estrogen exposure has been described as an important risk factor for breast cancer development and progression [69]. It has been documented that estrogen modulates angiogenesis via effects on endothelial cells under both physiologic and pathologic conditions [70]. Association of VEGF −460T/+405G/+936T haplotype with reduced risk of breast cancer has been reported in Chinese premenopausal women [47]. Among post-menopausal breast cancer patients, CCCCC haplotype of VEGF −2578C/A, −2489C/T, −460T/C, +405C/G and −7C/T polymorphisms was associated with reduced risk of distant metastases [71].

The CDTCCC haplotype was significantly associated with decrease risk of breast cancer in obese as well as in non obese patients compared to obese and non obese controls where as CDTGCC haplotype was significantly associated with increased risk of breast cancer in premenopausal obese patients. About 75.2% of patients and 72% of controls were obese in the present study. It has been hypothesized that hormonal mechanisms and metabolic factors are involved in the link between obesity and breast cancer. Insulin resistance and hyperinsulinemia have been reported to be associated with increased breast cancer risk and with worst prognosis in both pre and post menopausal women [72,73,74]. In mouse model, it has been demonstrated that over expression of VEGFA in adipose tissue provide protection against high fat diet induced obesity and insulin sensitivity [75, 76]. It has been documented that angiogenesis plays an important role in the regulation of adipogenesis [77]. VEGF has been described as an important angiogenic factor in adipose tissue and it regulates the development of new vessels required for the expansion of adipose tissue [76, 78]. It has been reported that adiponectin, a regulator of insulin resistance block angiogenesis by increasing the expression of TP53 and decreasing the expression of VEGF [79].

In the present study we predicted that VEGF −2578A allele of VEGF −2578C/A polymorphism abolished the binding site of GATA-2 transcription factor. The GATA family of transcription factors is regulator of gene expression in hematopoietic cells [80, 81]. Correlation of reduced GATA binding promoter activity has been documented with attenuation of VEGF mediated signaling [82]. G allele of VEGF +405C/G polymorphism created the binding site of MZF1 transcription factor. MZF1 transcription factor has been reported to be involved in transcriptional regulation during myelopoiesis [83]. Disruption of MZF1 transcription factor binding site by VEGF-634C (+405C) allele has also been reported in peripheral blood mononuclear cells [15]. It has been reported that substitution of C by G at +405 position in 5′-UTR may affect internal ribosome entry site (IRES) and increases the transcription of large isoform of VEGFA [84].

Polymorphisms of VEGFA have been reported to be associated with efficacy and toxicity of anti—VEGF agents [41, 85, 86]. Haplotype −460T/+405C/+936C haplotype was associated with better survival among Chinese breast cancer patients [87]. VEGF −2578A/−1154G/+405G haplotype was associated with marginally improved prognosis whereas haplotype −2578C/−1154G/+405G was significantly associated with adverse prognosis in HER2 positive breast cancer patients [88]. Apart from breast cancer, correlation of VEGF haplotypes with therapy response has also been documented in other cancer types. The CACC haplotype of VEGF −460T/C, −116G/A, +405C/G, and +936C/T polymorphism was significantly associated with worse survival in Korean gastric cancer patients [89]. In esophageal cancer, CGC haplotype of VEGF −460T/C, +405C/G and +936C/T polymorphism was associated with poorer outcome as compared to other haplotypes [90]. The AGCGC haplotype of VEGF −2578 C/A, −1154 G/A, −460T/C, +405 G/C and +936C/T polymorphisms was found to be associated with improved progression-free survival in epithelial ovarian cancer patients [91]. Haplotype −2578C/−460T/+405C/+936C and −2578C/−460T/+405C/+936T was associated with inferior response rate in metastatic colorectal cancer patients to first line XELOX treatment [92]. Thus, assessment of haplotypes of VEGF polymorphisms may have implications for aggressiveness and selection of patients suitable for anti-VEGF therapy in context of previously reported literature. The VEGF haplotypes in independent cohorts are insightful for identification of cancer risk.

Conclusions

We report for the first time that CDTCCC and CDTGCC haplotypes of VEGF −2578C/A, −2549I/D, −460T/C, +405C/G, −7C/T and +936C/T polymorphisms were significantly associated with breast cancer risk in North-West Indians. Further studies on multiethnic groups with larger sample size are required to confirm our results.

Availability of data and materials

All data generated in this study is included in Additional file 1: Table S1.

Abbreviations

VEGF:

Vascular endothelial growth factor

UTR:

Untranslated region

OR:

Odds ratio

References

  1. 1.

    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    CAS  Article  Google Scholar 

  2. 2.

    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–64.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18(1):4–25.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6(4):389–95.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Ferrara N. Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol. 1999;237:1–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Wu Y, Yanase K, Namisaki T, Kitade M, Yamazaki M. Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice. Hepatology. 2004;39(6):1517–24.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Roy H, Bhardwaj S, Ylä-Herttuala S. Biology of vascular endothelial growth factors. FEBS Lett. 2006;580(12):2879–87.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 1995;146(5):1029.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-κB activation in endothelial cells. J Biol Chem. 2001;276(10):7614–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Reinders ME, Fang JC, Wong W, Ganz P, Briscoe DM. Expression patterns of vascular endothelial growth factor in human cardiac allografts: association with rejection. Transplantation. 2003;76(1):224–30.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581–611.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Kimura Y, Morohashi S, Yoshizawa T, Suzuki T, Morohashi H, Sakamoto Y, Koyama M, Murata A, Kijima H, Hakamada K. Clinicopathological significance of vascular endothelial growth factor, thymidine phosphorylase and microvessel density in colorectal cancer. Mol Med Rep. 2016;13(2):1551–7.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Vincenti V, Cassano C, Rocchi M, Persico MG. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21. 3. Circulation. 1996;93(8):1493–5.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Brogan IJ, Khan N, Isaac K, Hutchinson JA, Pravica V, Hutchinson IV. Novel polymorphisms in the promoter and 5′ UTR regions of the human vascular endothelial growth factor gene. Hum Immunol. 1999;60(12):1245–9.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE. Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine. 2000;12(8):1232–5.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Akiri G, Nahari D, Finkelstein Y, Le SY, Elroy-Stein O, Levi BZ. Regulation of vascular endothelial growth factor (VEGF) expression is mediated by internal initiation of translation and alternative initiation of transcription. Oncogene. 1998;17(2):227–36.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Huez I, Créancier L, Audigier S, Gensac MC, Prats AC, Prats H. Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA. Mol Cell Biol. 1998;18(11):6178–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Taylor JG, Choi EH, Foster CB, Chanock SJ. Using genetic variation to study human disease. Trends Mol Med. 2001;7(11):507–12.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Renner W, Kotschan S, Hoffmann C, Obermayer-Pietsch B, Pilger E. A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J Vasc Res. 2000;37(6):443–8.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, Inoue I, Katayama S. A common polymorphism in the 5′-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes. 2002;51(5):1635–9.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Mohammadi M, Ollier WE, Hutchinson IV. A functional association study of VEGF gene promoter polymorphisms with VEGF expression by stimulated pbm cells. Hum Immunol. 2003;10(64):S125.

    Article  Google Scholar 

  22. 22.

    Stevens A, Soden J, Brenchley PE, Ralph S, Ray DW. Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. Can Res. 2003;63(4):812–6.

    CAS  Google Scholar 

  23. 23.

    Adams J, Carder PJ, Downey S, Forbes MA, MacLennan K, Allgar V, Kaufman S, Hallam S, Bicknell R, Walker JJ, Cairnduff F. Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Can Res. 2000;60(11):2898–905.

    CAS  Google Scholar 

  24. 24.

    Gasparini G. Prognostic value of vascular endothelial growth factor in breast cancer. Oncologist. 2000;5:37–44.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP. Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Can Res. 1996;56(9):2013–6.

    CAS  Google Scholar 

  26. 26.

    Guidi AJ, Schnitt SJ, Fischer L, Tognazzi K, Harris JR, Dvorak HF, Brown LF. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in patients with ductal carcinoma in situ of the breast. Cancer. 1997;80(10):1945–53.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Koukourakis MI, Papazoglou D, Giatromanolaki A, Bougioukas G, Maltezos E, Siviridis E. VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer. 2004;46(3):293–8.

    PubMed  Article  Google Scholar 

  28. 28.

    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Willett CG, Boucher Y, Di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10(2):145–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Jain RK. Antiangiogenic therapy for cancer: current and emerging concepts. Oncology (Williston Park). 2005;19(4 Suppl 3):7–16.

    Google Scholar 

  31. 31.

    Clark AG. The role of haplotypes in candidate gene studies. Genet Epidemiol. 2004;27(4):321–33.

    PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Kapahi R, Manjari M, Uppal MS, Singh NR, Sambyal V, Guleria K. Association of− 2549 insertion/deletion polymorphism of vascular endothelial growth factor with breast cancer in North Indian patients. Genet Test Mol Biomarkers. 2013;17(3):242–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Adeli K, Ogbonna G. Rapid purification of human DNA from whole blood for potential application in clinical chemistry laboratories. Clin Chem. 1990;36(2):261–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Kapahi R, Manjari M, Sudan M, Uppal MS, Singh NR, Sambyal V, Guleria K. Association of +405C>G and +936C>T polymorphisms of the vascular endothelial growth factor gene with sporadic breast cancer in North Indians. Asian Pac J Cancer Prev. 2014;15(1):257–63.

    PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Kapahi R, Guleria K, Sambyal V, Manjari M, Sudan M, Uppal MS, Singh NR. Association of VEGF and VEGFR1 polymorphisms with breast cancer risk in North Indians. Tumor Biol. 2015;36(6):4223–34.

    CAS  Article  Google Scholar 

  36. 36.

    Sole X, Guino E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22(15):1928–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Al Balawi IA, Mir R, Abu-Duhier FM. Potential impact of vascular endothelial growth factor gene variation (-2578C> A) on breast cancer susceptibility in Saudi Arabia: a case–control study. Asian Pac J Cancer Prev. 2018;19(4):1135.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Rezaei M, Hashemi M, Sanaei S, Mashhadi MA, Taheri M. Association between vascular endothelial growth factor gene polymorphisms with breast cancer risk in an Iranian population. Breast Cancer (Auckl). 2016;10:85–91.

    CAS  Google Scholar 

  39. 39.

    Rahoui J, Laraqui A, Sbitti Y, Touil N, Ibrahimi A, Ghrab B, Al Bouzidi A, Rahali DM, Dehayni M, Ichou M, Zaoui F. Investigating the association of vascular endothelial growth factor polymorphisms with breast cancer: a Moroccan case–control study. Med Oncol. 2014;31(9):193.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  40. 40.

    Sa-Nguanraksa D, Chuangsuwanich T, Pongpruttipan T, Kummalue T, Rojananin S, Ratanawichhitrasin A, Prasarttong-Osoth P, Chuthatisith S, Pisarnturakit P, Aeumrithaicharoenchok W, Rushatamukayanunt P. Vascular endothelial growth factor-634G/C polymorphism is associated with increased breast cancer risk and aggressiveness. Mol Med Rep. 2013;8(4):1242–50.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Schneider BP, Radovich M, Sledge GW, Robarge JD, Li L, Storniolo AM, Lemler S, Nguyen AT, Hancock BA, Stout M, Skaar T. Association of polymorphisms of angiogenesis genes with breast cancer. Breast Cancer Res Treat. 2008;111(1):157–63.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Langsenlehner T, Langsenlehner U, Renner W, Krippl P, Mayer R, Wascher TC, Kapp KS. Single nucleotide polymorphisms and haplotypes in the gene for vascular endothelial growth factor and risk of prostate cancer. Eur J Cancer. 2008;44(11):1572–6.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Pharoah PD, Antoniou AC, Easton DF, Ponder BA. Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med. 2008;358(26):2796–803.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Jacobs EJ, Feigelson HS, Bain EB, Brady KA, Rodriguez C, Stevens VL, Patel AV, Thun MJ, Calle EE. Polymorphisms in the vascular endothelial growth factor gene and breast cancer in the Cancer Prevention Study II cohort. Breast Cancer Res. 2006;8(2):R22.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Jin Q, Hemminki K, Enquist K, Lenner P, Grzybowska E, Klaes R, Henriksson R, Chen B, Pamula J, Pekala W, Zientek H. Vascular endothelial growth factor polymorphisms in relation to breast cancer development and prognosis. Clin Cancer Res. 2005;11(10):3647–53.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Balasubramanian SP, Cox A, Cross SS, Higham SE, Brown NJ, Reed MW. Influence of VEGF-A gene variation and protein levels in breast cancer susceptibility and severity. Int J Cancer. 2007;121(5):1009–16.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Kataoka N, Cai Q, Wen W, Shu XO, Jin F, Gao YT, Zheng W. Population-based case–control study of VEGF gene polymorphisms and breast cancer risk among Chinese women. Cancer Epidemiol Biomarkers Prev. 2006;15(6):1148–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    James R, Ramesh G, Krishnamoorthy L, Bhagat R, Chadaga S, Deshmane V, Ramaswamy G. Prevalence of+ 405G> C,− 1154G> A vascular endothelial growth factor polymorphism in breast cancer. Indian J Clin Biochem. 2014;29(1):21–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Rani J, Rahul B, Ramesh G, Krishnamoorthy L, Shilpa C, Ramaswamy G, Deshmane V. Association of vascular endothelial growth factor single nucleotide polymorphisms on the prognosis of breast cancer patients. Indian J Cancer. 2014;51(4):512.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Luo T, Chen L, He P, Hu QC, Zhong XR, Sun Y, Yang YF, Tian TL, Zheng H. Vascular endothelial growth factor (VEGF) gene polymorphisms and breast cancer risk in a Chinese population. Asian Pac J Cancer Prev. 2013;14(4):2433–7.

    PubMed  Article  Google Scholar 

  51. 51.

    Oliveira C, Lourenço GJ, Silva PM, Cardoso-Filho C, Favarelli MH, Gonçales NS, Gurgel MS, Lima CS. Polymorphisms in the 5′-and 3′-untranslated region of the VEGF gene and sporadic breast cancer risk and clinicopathologic characteristics. Tumor Biol. 2011;32(2):295–300.

    CAS  Article  Google Scholar 

  52. 52.

    Absenger G, Szkandera J, Stotz M, Pichler M, Winder T, Langsenlehner T, Langsenlehner U, Samonigg H, Renner W, Gerger A. A common and functional gene variant in the vascular endothelial growth factor a predicts clinical outcome in early-stage breast cancer. Mol Carcinog. 2013;52(S1):96–102.

    Article  CAS  Google Scholar 

  53. 53.

    Rodrigues P, Furriol J, Tormo E, Ballester S, Lluch A, Eroles P. The single-nucleotide polymorphisms+ 936 C/T VEGF and− 710 C/T VEGFR1 are associated with breast cancer protection in a Spanish population. Breast Cancer Res Treat. 2012;133(2):769–78.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Lin GT, Tseng HF, Yang CH, Hou MF, Chuang LY, Tai HT, Tai MH, Cheng YH, Wen CH, Liu CS, Huang CJ. Combinational polymorphisms of seven CXCL12-related genes are protective against breast cancer in Taiwan. OMICS. 2009;13(2):165–72.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Jakubowska A, Gronwald J, Menkiszak J, Górski B, Huzarski T, Byrski T, Edler L, Lubiński J, Scott RJ, Hamann U. The VEGF_936_C> T 3′ UTR polymorphism reduces BRCA1-associated breast cancer risk in Polish women. Cancer Lett. 2008;262(1):71–6.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Eroğlu A, Öztürk A, Cam R, Akar N. Vascular endothelial growth factor gene 936 C/T polymorphism in breast cancer patients. Med Oncol. 2008;25(1):54–5.

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Haas J, Samonigg H. A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. Int J Cancer. 2003;106(4):468–71.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Kidd LR, Brock GN, VanCleave TT, Benford ML, Lavender NA, Kruer TL, Wittliff JL. Angiogenesis-associated sequence variants relative to breast cancer recurrence and survival. Cancer Causes Control. 2010;21(10):1545–57.

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Lee SJ, Lee SY, Jeon HS, Park SH, Jang JS, Lee GY, Son JW, Kim CH, Lee WK, Kam S, Park RW. Vascular endothelial growth factor gene polymorphisms and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev. 2005;14(3):571–5.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Zhai R, Liu G, Asomaning K, Su L, Kulke MH, Heist RS, Nishioka NS, Lynch TJ, Wain JC, Lin X, Christiani DC. Genetic polymorphisms of VEGF, interactions with cigarette smoking exposure and esophageal adenocarcinoma risk. Carcinogenesis. 2008;29(12):2330–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Zhai R, Liu G, Zhou W, Su L, Heist RS, Lynch TJ, Wain JC, Asomaning K, Lin X, Christiani DC. Vascular endothelial growth factor genotypes, haplotypes, gender, and the risk of non–small cell lung cancer. Clin Cancer Res. 2008;14(2):612–7.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Jannuzzi AT, Özhan G, Yanar HT, Alpertunga B. VEGF gene polymorphisms and susceptibility to colorectal cancer. Genet Test Mol Biomarkers. 2015;19(3):133–7.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Ben Wafi S, Kallel A, Ben Fradj MK, Sallemi A, Ben Rhouma S, Ben Halima M, Sanhaji H, Nouira Y, Jemaa R, Feki M. Haplotype-based association of Vascular Endothelial Growth Factor gene polymorphisms with urothelial bladder cancer risk in Tunisian population. J Clin Lab Anal. 2018;32(9):e22610.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    Jaiswal PK, Tripathi N, Shukla A, Mittal RD. Association of single nucleotide polymorphisms in vascular endothelial growth factor gene with bladder cancer risk. Med Oncol. 2013;30(2):509.

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Prakash S, Prasad N, Sharma RK, Faridi RM, Agrawal S. Vascular endothelial growth factor gene polymorphisms in North Indian patients with end stage renal disease. Cytokine. 2012;58(2):261–6.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Janardhan B, Vaderhobli S, Bhagat R, Chennagiri Srinivasamurthy P, Venketeshiah Reddihalli P, Gawari R, Krishnamoorthy L. Investigating impact of vascular endothelial growth factor polymorphisms in epithelial ovarian cancers: a study in the Indian population. PLoS ONE. 2015;10(7):e0131190.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. 67.

    Naikoo NA, Afroze D, Rasool R, Shah S, Ahangar AG, Bhat IA, Qasim I, Siddiqi MA, Shah ZA. SNP and haplotype analysis of vascular endothelial growth factor (VEGF) gene in lung cancer patients of Kashmir. Asian Pac J Cancer Prev. 2017;18(7):1799.

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Mohanty SS, Mohanty PK. Obesity as potential breast cancer risk factor for postmenopausal women. Genes Dis. 2019;8:117–23.

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Lapidus RG, Nass SJ, Davidson NE. The loss of estrogen and progesterone receptor gene expression in human breast cancer. J Mammary Gland Biol Neoplasia. 1998;3(1):85–94.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Losordo DW, Isner JM. Estrogen and angiogenesis: a review. Arterioscler Thromb Vasc Biol. 2001;21(1):6–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. 71.

    Langsenlehner U, Hofmann G, Renner W, Gerger A, Krenn-Pilko S, Thurner EM, Krippl P, Langsenlehner T. Association of vascular endothelial growth factor—a gene polymorphisms and haplotypes with breast cancer metastases. Acta Oncol. 2015;54(3):368–76.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, Hartwick W, Hoffman B, Hood N. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol. 2002;20(1):42–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Morimoto LM, White E, Chen Z, Chlebowski RT, Hays J, Kuller L, Lopez AM, Manson J, Margolis KL, Muti PC, Stefanick ML. Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative (United States). Cancer Causes Control. 2002;13(8):741–51.

    PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Schairer C, Hill D, Sturgeon SR, Fears T, Pollak M, Mies C, Ziegler RG, Hoover RN, Sherman ME. Serum concentrations of IGF-I, IGFBP-3 and c-peptide and risk of hyperplasia and cancer of the breast in postmenopausal women. Int J Cancer. 2004;108(5):773–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Elias I, Franckhauser S, Ferré T, Vilà L, Tafuro S, Muñoz S, Roca C, Ramos D, Pujol A, Riu E, Ruberte J. Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. Diabetes. 2012;61(7):1801–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Sun K, Asterholm IW, Kusminski CM, Bueno AC, Wang ZV, Pollard JW, Brekken RA, Scherer PE. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc Natl Acad Sci. 2012;109(15):5874–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Xue Y, Petrovic N, Cao R, Larsson O, Lim S, Chen S, Feldmann HM, Liang Z, Zhu Z, Nedergaard J, Cannon B. Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab. 2009;9(1):99–109.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Cao Y. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nat Rev Drug Discov. 2010;9(2):107–15.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    Khan S, Shukla S, Sinha S, Meeran SM. Role of adipokines and cytokines in obesity-associated breast cancer: therapeutic targets. Cytokine Growth Factor Rev. 2013;24(6):503–13.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M, Alt FW, Orkin SH. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature. 1994;371(6494):221–6.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Shimizu R, Yamamoto M. Gene expression regulation and domain function of hematopoietic GATA factors. Semin Cell Dev Biol. 2005;16(1):129–36.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Minami T, Murakami T, Horiuchi K, Miura M, Noguchi T, Miyazaki JI, Hamakubo T, Aird WC, Kodama T. Interaction between hex and GATA transcription factors in vascular endothelial cells inhibits flk-1/KDR-mediated vascular endothelial growth factor signaling. J Biol Chem. 2004;279(20):20626–35.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Lenny N, Westendorf JJ, Hiebert SW. Transcriptional regulation during myelopoiesis. Mol Biol Rep. 1997;24(3):157.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Huez I, Bornes S, Bresson D, Créancier L, Prats H. New vascular endothelial growth factor isoform generated by internal ribosome entry site-driven CUG translation initiation. Mol Endocrinol. 2001;15(12):2197–210.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Etienne-Grimaldi MC, Formento P, Degeorges A, Pierga JY, Delva R, Pivot X, Dalenc F, Espié M, Veyret C, Formento JL, Francoual M. Prospective analysis of the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-based therapy in metastatic breast cancer patients. Br J Clin Pharmacol. 2011;71(6):921–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Formica V, Palmirotta R, Del Monte G, Savonarola A, Ludovici G, De Marchis ML, Grenga I, Schirru M, Guadagni F, Roselli M. Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab. Int J Colorectal Dis. 2011;26(2):143–51.

    PubMed  Article  Google Scholar 

  87. 87.

    Lu H, Shu XO, Cui Y, Kataoka N, Wen W, Cai Q, Ruan ZX, Gao YT, Zheng W. Association of genetic polymorphisms in the VEGF gene with breast cancer survival. Can Res. 2005;65(12):5015–9.

    CAS  Article  Google Scholar 

  88. 88.

    Maae E, Andersen RF, Steffensen KD, Jakobsen EH, Brandslund I, Sørensen FB, Jakobsen A. Prognostic impact of VEGFA germline polymorphisms in patients with HER2-positive primary breast cancer. Anticancer Res. 2012;32(9):3619–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Kim JG, Sohn SK, Chae YS, Cho YY, Bae HI, Yan G, Park JY, Lee MH, Chung HY, Yu W. Vascular endothelial growth factor gene polymorphisms associated with prognosis for patients with gastric cancer. Ann Oncol. 2007;18(6):1030–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Bradbury PA, Zhai R, Ma C, Xu W, Hopkins J, Kulke MJ, Asomaning K, Wang Z, Su L, Heist RS, Lynch TJ. Vascular endothelial growth factor polymorphisms and esophageal cancer prognosis. Clin Cancer Res. 2009;15(14):4680–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Steffensen KD, Waldstrøm M, Brandslund I, Jakobsen A. The relationship of VEGF polymorphisms with serum VEGF levels and progression-free survival in patients with epithelial ovarian cancer. Gynecol Oncol. 2010;117(1):109–16.

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Hansen TF, Spindler KG, Andersen RF, Lindebjerg J, Brandslund I, Jakobsen A. The predictive value of genetic variations in the vascular endothelial growth factor A gene in metastatic colorectal cancer. Pharmacogenomics J. 2011;11(1):53–60.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

We thank the patients and the healthy control individuals for their participation.

Funding

This study was supported by the DBT grant BT/PR 13252/GBD/27/236/2009 and DST-PURSE grant sanctioned to VS and KG. The funders had no role in the designing of the study or in the collection of samples, analysis of data or preparation of the manuscript.

Author information

Affiliations

Authors

Contributions

KG and VS conceptualized and designed the study. RK and KG performed the experiments. KG and VS analyzed the results and prepared the manuscript. MM, MS, MSU and NRS did clinical diagnosis and histopathological classification of patients and also helped in collection of blood samples of breast cancer patients. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Kamlesh Guleria.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Institutional Ethics Committee of Guru Nanak Dev University, Amritsar, Punjab, India. The consent form was in English as well as in local language of the region. The literate subjects gave a written informed consent with a signature. The illiterate subjects have their consent with a thumb impression on the form in presence of a witness (their relative or accompanying person).

Consent for publication

Not applicable.

Competing interests

Kamlesh Guleria, corresponding author and co-author Vasudha Sambyal are Associate Editors of BMC Medical Genomics Journal. Rest of the other authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1.

In silico pathway analysis based on chromosomal instability in breast cancer patients.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sambyal, V., Guleria, K., Kapahi, R. et al. Association of VEGF haplotypes with breast cancer risk in North-West Indians. BMC Med Genomics 14, 209 (2021). https://doi.org/10.1186/s12920-021-01060-4

Download citation

Keywords

  • VEGF
  • Polymorphism
  • Haplotype
  • Breast cancer