Abstract
BackgroundThe VEGF-independent angiogenic signaling plays an important role in the development of colorectal cancer (CRC). However, its implication in the clinical outcome of CRC has not been reported. This study aimed to investigate the association between genetic variations in several major VEGF-independent signaling pathway genes and the overall survival of CRC patients.MethodsSeven single nucleotide polymorphisms (SNPs) in four important VEGF-independent angiogenic genes (ANGPT1, AMOT, DLL4 and ENG) were genotyped in a Chinese population with 408 CRC patients.ResultsOne SNP, rs1954727 in ANGPT1, was significantly associated with CRC overall survival. Compared to patients with the homozygous wild-type genotype of rs1954727, those with heterozygous and homozygous variant genotypes exhibited a favorable overall survival with a hazard ratio (HR) of 0.89 (95% confidence interval [CI] 0.55–1.43, P = 0.623), and 0.32 (95% CI 0.15–0.71, P = 0.005), respectively (P trend = 0.008). In stratified analysis, this association remained significant in patients receiving chemotherapy (P trend = 0.012), but not in those without chemotherapy. We further evaluated the effects of chemotherapy on CRC survival that was stratified by rs1954727 genotypes. We found that chemotherapy resulted in a significantly better overall survival in the CRC patients (HR = 0.44, 95% CI 0.26–0.75, P = 0.002), which was especially prominent in those patients with the heterozygous genotype of rs1954727 (HR = 0.45, 95%CI 0.22–0.92, P = 0.028). ConclusionOur data suggest that rs1954727 in ANGPT1 gene might be a prognostic biomarker for the overall survival of CRC patients, especially in those receiving chemotherapy, a finding that warrants validation in larger independent populations.
Highlights
Worldwide, colorectal cancer (CRC) is the third most common malignancy and the fourth leading cause of cancer death with an estimated 1,234,000 new cases and 608,000 deaths in 2008 [1]
The wide resistance to the antiangiogenic therapies targeting the vascular endothelial growth factors (VEGFs) pathway stimulated the search for treatments targeting the VEGF-independent angiogenesis pathway [12,13], such as pro-angiogenic pathways mediated by angiopoietins/TIE-2 and Delta/Notch [14,15], as well as antiangiogenic pathways mediated by angiomotin and endoglin proteins [16,17]
Patients Characteristics A total of 408 surgically resected CRC patients were included in this study, with an average age of 59.4 years and mean body mass index (BMI) of 22.7
Summary
Colorectal cancer (CRC) is the third most common malignancy and the fourth leading cause of cancer death with an estimated 1,234,000 new cases and 608,000 deaths in 2008 [1]. The generation of new blood vessels, is a crucial cellular process that influences tumor cell growth, invasion, local-regional recurrence, and metastatic spread of CRC, making it an attractive target for anticancer drug development [10].The tumor cell growth, invasion, and metastases are heavily influenced by the balance of functions of endogenous angiogenic and antiangiogenic factors [10]. The functional inhibitors of VEGF and VEGFRs, such as anti-VEGF neutralizing antibody and small molecules that block the tyrosine kinase activity of VEGFRs, have been approved as anti-angiogenesis therapies for many cancers, including CRC [12]. The VEGF-independent angiogenic signaling plays an important role in the development of colorectal cancer (CRC). This study aimed to investigate the association between genetic variations in several major VEGF-independent signaling pathway genes and the overall survival of CRC patients
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