Tumor angiogenesis is known to support the spread and invasion of tumor cells, allow distant organ metastasis and to result in poorer prognoses and increased mortality. Since vascular endothelial growth factor-A (VEGF-A) is the major regulator of angiogenesis, in the present study the associations of the VEGF-A +405G>C and −460C>T polymorphisms with risk, primary tumor location, prognosis and metastasis of colorectal cancer (CRC) were investigated in Turkish subjects.
Material and Methods:
A total of 153 subjects consist of 74 controls and 79 CRC diagnosed patients were included in the study. VEGF-A +405G>C and −460C>T polymorphisms were analyzed using the Agena MassARRAY platform.
Results:
The VEGF +405GC+CC genotypes were found to be significantly associated with left colon cancer (unadjusted OR = 5.208 95% CI: 1.064-25.496, p = 0.04). The VEGF −460TT and CT+TT genotypes were associated with reduced liver metastasis risk (OR = 0.080 95% CI: 0.009-0.689 p = 0.02 and OR = 0.191 95% CI: 0.039-0.925, p = 0.04, respectively). Patients with the VEGF +405GG genotype showed longer progression-free survival in response to bevacizumab treatment (Log rank = 6.92, p = 0.03).
Conclusion:
According to our results, the VEGF +405G>C and −460C>T polymorphisms were found to be associated with CRC prognosis, sidedness and metastases. Our findings need to be replicated in further studies.
Get full access to this article
View all access options for this article.
References
1.
AltomareDF, RotelliMT, PentimoneA, et al. (2007) Tissue factor and vascular endothelial growth factor expression in colorectal cancer: relation with cancer recurrence. Colorectal Dis, 9:133-138.
2.
AntonacopoulouAG, KottorouAE, DimitrakopoulosFID, et al. (2012) VEGF polymorphisms may be associated with susceptibility to colorectal cancer: a case-control study. Cancer Biomark, 10:213-217.
3.
AwataT, InoueK, KuriharaS, et al. (2002) A common polymorphism in the 5′-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes, 51:1635-1639.
4.
BendardafR, BuhmeidaA, HilskaM, et al. (2008) VEGF-1 expression in colorectal cancer is associated with disease localization, stage, and long-term disease-specific survival. Anticancer Res, 28:3865-3870.
5.
BendardafR, El-SerafiA, SyrjänendK, et al. (2017) The effect of vascular endothelial growth factor-1 expression on survival of advanced colorectal cancer patients. Libyan J Med, 12:1290741.
6.
BenedixF, KubeR, MeyerF, et al. (2010) Comparison of 17,641 patients with right-and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum, 53:57-64.
7.
BotrelTEA, de Oliveira ClarkLG, PaladiniL, ClarkOAC (2016) Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer, 16:1-19.
8.
CarmelietP (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med, 6:389-395.
9.
ChaeYS, KimJG, SohnSK, et al. (2008) Association of vascular endothelial growth factor gene polymorphisms with susceptibility and clinicopathologic characteristics of colorectal cancer. J Korean Med Sci, 23:421-427.
10.
ChengJZ, ChenJJ, XueK, et al. (2018) Clinicopathologic and prognostic significance of VEGF, JAK2 and STAT3 in patients with nasopharyngeal carcinoma. Cancer Cell Int, 18:1-9.
11.
DassoulasK, GazouliM, RizosS, et al. (2009) Common polymorphisms in the vascular endothelial growth factor gene and colorectal cancer development, prognosis, and survival. Mol Carcinog, 48:563-569.
12.
DinamiR, PorruM, AmoreoCA, et al. (2020) TRF2 and VEGF-A: an unknown relationship with prognostic impact on survival of colorectal cancer patients. J Exp Clin Cancer Res, 39:1-13.
13.
do Espírito SantoGF, GaleraBB, DuarteEC, et al. (2017) Prognostic significance of vascular endothelial growth factor polymorphisms in colorectal cancer patients. World J Gastrointest Oncol, 9:78.
14.
DvorakHF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol, 20:4368-4380.
15.
FerlayJ, SoerjomataramI, ErvikM, et al. (2013) GLOBOCAN 2012 v1. 0 (2013) Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 (Internet). International Agency for Research on Cancer, Lyon,France.
16.
FerraraN, GerberHP, LeCouterJ. (2003) The Biology of VEGF and its Receptors. Nat Med, 9:669-676.
17.
FerroniP, SpilaA, MartiniF, et al. (2005) Prognostic value of vascular endothelial growth factor tumor tissue content of colorectal cancer. Oncology, 69:145-153.
18.
FrezzettiD, GalloM, MaielloMR, et al. (2017) VEGF as a potential target in lung cancer. Expert Opin Ther Targets, 21:959-966.
19.
FuZZ, SunXD, LiP, et al. (2014) Relationship between serum VEGF level and radiosensitivity of patients with nonsmall cell lung cancer among asians: a meta-analysis. DNA Cell Biol, 33:426-437.
20.
GabrielS, ZiaugraL, TabbaaD (2009) SNP genotyping using the Sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet, 60:2-12.
21.
GrassadoniaA, Di MarinoP, FicorellaC, et al. (2019) Impact of primary tumor location in patients with RAS wild-type metastatic colon cancer treated with first-line chemotherapy plus anti-EGFR or anti-VEGF monoclonal antibodies: a retrospective multicenter study. J Cancer, 10:5926.
22.
GuoQ, DaiSB, ShenF, et al. (2014) VEGF +405G/C (rs2010963) polymorphisms and digestive system cancer risk: a meta-analysis. Tumor Biol, 35:4977-4982.
23.
GuptaMK, QinRY (2003) Mechanism and its regulation of tumouqr induced angiogenesis. World J Gastroenterol, 9:1144-1155.
24.
HanahanD, FolkmanJ (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86:353-364.
25.
HansenTF, SpindlerKG, AndersenRF, et al. (2011) The predictive value of genetic variations in the vascular endothelial growth factor A gene in metastatic colorectal cancer. Pharmacogenomics J, 11:53-60.
HicklinDJ, EllisLM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol, 23:1011-1027.
28.
HurwitzH, FehrenbacherL, NovotnyW, et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Eng J Med, 350:2335-2342.
29.
InnocentiF, JiangC, SibleyAB, et al. (2018) Genetic variation determines VEGF-A plasma levels in cancer patients. Sci Rep, 8:1-9.
30.
JangMJ, JeonYJ, KimJW, et al. (2013a) Association of VEGF and KDR single nucleotide polymorphisms with colorectal cancer susceptibility in Koreans. Mol Carcinog, 52:60-69.
31.
JangMJ, KimJW, JeonYJ, et al. (2013b) Prognostic significance of vascular endothelial growth factor gene polymorphisms in patients with colorectal cancer. Int J Clin Oncol, 18:1032-1041.
32.
JannuzziAT, ÖzhanG, YanarHT, AlpertungaB (2015) VEGF gene polymorphisms and susceptibility to colorectal cancer. Genet Test Mol Biomark, 19:133-137.
33.
KoukourakisMI, PapazoglouD, GiatromanolakiA, et al. (2004) VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung cancer, 46:293-298.
34.
KoutrasAK, AntonacopoulouAG, EleftherakiAG, et al. (2012) Vascular endothelial growth factor polymorphisms and clinical outcome in colorectal cancer patients treated with irinotecan-based chemotherapy and bevacizumab. Pharmacogenomics J, 12:468-475.
35.
KumarV, AbbasAK, Fausto N (2004) Robbins and Cotran Pathologic Basis ofDisease. 7th. ed. Saunders; Elsevier Inc.,Philadelphia.
36.
KuramochiH, HayashiK, UchidaK, et al. (2006) Vascular endothelial growth factor messenger RNA expression level is preserved in liver metastases compared with corresponding primary colorectal cancer. Clin Cancer Res, 12:29-33.
37.
LacinS, YalcinS (2020) The prognostic value of circulating VEGF-A level in patients with hepatocellular cancer. Technol Cancer Res Treat, 19:1533033820971677.
38.
LeeGH, MalietzisG, AskariA, et al. (2015) Is right-sided colon cancer different to left-sided colorectal cancer?-a systematic review. Eur J Surg Oncol, 41:300-308.
39.
LeeJC, ChowNH, WangST, HuangSM (2000) Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients. Eur J Cancer, 36:748-753.
40.
LevinB, LiebermanDA, McFarlandB, et al. (2008) Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin, 58:130-160.
41.
LiS, WangL, MengY, et al. (2017) Increased levels of LAPTM4B, VEGF and survivin are correlated with tumor progression and poor prognosis in breast cancer patients. Oncotarget, 8:41282.
42.
LiT, KangG, WangT, HuangHE (2018) Tumor angiogenesis and anti-angiogenic gene therapy for cancer. Oncol Lett, 16:687-702.
43.
LoupakisF, CremoliniC, FioravantiA, et al. (2011a) Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer, 104:1262-1269.
44.
LoupakisF, CremoliniC, YangD, et al. (2013) Prospective validation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. PLoS One, 8:e66774.
45.
LoupakisF, RuzzoA, SalvatoreL, et al. (2011b) Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer. BMC Cancer, 11:1-9.
46.
MacarullaT, MontagutC, Sánchez-MartinFJ, et al. (2020) The role of PIGF blockade in the treatment of colorectal cancer: overcoming the pitfalls. Expert Opin Biol Ther, 20:15-22.
47.
MalteseP, CanestrariE, RuzzoA, et al. (2009) VEGF gene polymorphisms and susceptibility to colorectal cancer disease in Italian population. Int J Colorectal Dis, 24:165-170.
48.
MashimaT, WakatsukiT, KawataNJ, et al. (2021) Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo. Sci Rep, 11:1-12.
49.
MlecnikB, BindeaG, KirilovskyA, et al. (2016) The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med, 8:327ra26.
50.
MousaSA (2000) Mechanisms of Angiogenesis: Potential Therapeutic Targets. Eurekah.com/Landes Bioscience, Georgetown, WA, USA.
51.
NovilloA, GaibarM, Romero-LorcaA, et al. (2020) Efficacy of bevacizumab-containing chemotherapy in metastatic colorectal cancer and CXCL5 expression: six case reports. World J Gastroenterol, 26:1979.
52.
O-CharoenratP (2014) Vascular endothelial growth factor polymorphisms affect gene expression and tumor aggressiveness in patients with breast cancer. Mol Med Rep, 9:1044-1048.
53.
PanderJ, WesselsJA, GelderblomH, et al. (2011) Pharmacogenetic interaction analysis for the efficacy of systemic treatment in metastatic colorectal cancer. Ann Oncol, 22:1147-1153.
54.
PapachristosA, KemosP, KatsilaT, et al. (2019) VEGF-A and ICAM-1 gene polymorphisms as predictors of clinical outcome to first-line bevacizumab-based treatment in metastatic colorectal cancer. Int J Mol Sci, 20:5791.
55.
PlastirasA, IosifE, GeorgiouG, et al. (2019) Right versus left Colon cancer: is there a difference in outcomes?. World J Colorectal Surg, 8:14.
56.
RajabiM, MousaSA (2017) The role of angiogenesis in cancer treatment. Biomedicines, 5:34.
57.
RieraP, VirgiliAC, SalazarJ, et al. (2018) Genetic variants in the VEGF pathway as prognostic factors in stages II and III colon cancer. Pharmacogenomics J, 18:556-564.
58.
RisauW (1997) Mechanisms of angiogenesis. Nature, 386:671-674.
59.
RuanWC, CheYP, DingL, LiHF (2018) Efficacy and toxicity of addition of bevacizumab to chemotherapy in patients with metastatic colorectal cancer. Comb Chem High Throughput Screen, 21:718-724.
60.
Sa-NguanraksaD, ChuangsuwanichT, PongpruttipanT, et al. (2013) Vascular endothelial growth factor 634G/C polymorphism is associated with increased breast cancer risk and aggressiveness. Mol Med Rep, 8:1242-1250
61.
SlatteryML, LundgreenA, WolffRK (2014) VEGFA, FLT1, KDR and colorectal cancer: assessment of disease risk, tumor molecular phenotype, and survival. Mol Carcinog, 53:E140-E150.
62.
SopoM, AnttilaM, HämäläinenK, et al. (2019) Expression profiles of VEGF-A, VEGF-D and VEGFR1 are higher in distant metastases than in matched primary high grade epithelial ovarian cancer. BMC Cancer, 19:1-12.
63.
StintzingS, TejparS, GibbsP, et al. (2017) Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes. Eur J Cancer, 84:69-80.
64.
SzajewskiM, KruszewskiWJ, LakomyJ, et al. (2014) VEGF-C and VEGF-D overexpression is more common in left-sided and well-differentiated colon adenocarcinoma. Oncol Rep, 31:125-130.
65.
TorreLA, BrayF, SiegelRL, et al. (2015) Global cancer statistics, 2012. CA Cancer J Clin, 65:87-108.
66.
UliviP, ScarpiE, PassardiA, et al. (2015) eNOS polymorphisms as predictors of efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer: data from a randomized clinical trial. J Transl Med, 13:1-10.
67.
Van CutsemE, PaccardC, ChironM, TaberneroJ (2020) Impact of prior bevacizumab treatment on VEGF-A and PlGF levels and outcome following second-line aflibercept treatment: biomarker post hoc analysis of the VELOUR trial. Clin Cancer Res, 26:717-725.
68.
YamamoriM, SakaedaT, NakamuraT, et al. (2004) Association of VEGF genotype with mRNA level in colorectal adenocarcinomas. Biochem Biophys Res Commun, 325:144-150.
69.
ZhaoZ, BaC, WangW, et al. (2012) Vascular endothelial growth factor (VEGF) gene polymorphisms and colorectal cancer: a meta-analysis of epidemiologic studies. Genet Test Mol Biomark, 16:1390-1394.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
