SDF-1α G801A Polymorphism Predicts Lymph Node Metastasis in Stage T3 Colorectal Cancer

The SDF-1/CXCR4 axis plays an important role in cancer metastasis. SDF1 alpha genetic polymorphisms, including SDF1 alpha-G801A, have been associated with increased cancer risk and may be predictive of distant metastasis. The present study compared the frequency of 6 SDF1 alpha single-nucleotide polymorphisms (SNPs) in patients with colorectal cancer (CRC) with and without lymph node (LN) metastasis and determined whether fibroblasts with different SDF-1 alpha genotypes influenced cancer cell proliferation and migration. The study enrolled 424 patients with primary T3 stage CRC, with and without lymph node metastasis, and a median follow-up of 48 months. The polymerase chain reaction-sequence specific primers (PCR-SSP) technique was used to identify polymorphisms. Fibroblasts were harvested from 14 patients with stage II CRC and fibroblast-mediated enhancement of cancer cell proliferation and migration was evaluated. Only the SDF1 alpha-G801A polymorphism was associated with LN metastasis. The frequency of GA/AA genotypes was significantly higher in patients with LN metastasis (54.8%) than in patients without LN metastasis (40.7%). In the latter group, disease-free survival was shorter in patients with the GA/AA genotype (74%) than in patients with the GG genotype (87.6%). In patients with LN metastasis, disease-free survival was similar regardless of genotype. Expression of SDF-1 alpha mRNA in GA/AA fibroblasts was three times that in GG fibroblasts. GA/AA (but not GG) fibroblasts enhanced colon cancer cell (HCT116) proliferation and migration. These effects were blocked by an SDF-1 alpha neutralizing antibody. The SDF1 alpha-G801A polymorphism may increase expression of SDF-1 alpha mRNA and be a predictive marker of lymph node metastasis in colorectal cancer.