Polymorphisms in the hypoxia-inducible factor-1alpha gene confer susceptibility to pancreatic cancer.

摘要

The transcription factor hypoxia-inducible factor-1 (HIF-1) has alpha and beta subunits. Recent studies have shown that the HIF-1alpha gene may have C1772T and G1790A single nucleotide polymorphisms (SNPs). These SNPs may increase the stability and activity of HIF-1alpha. In the present study, we looked for these SNPs by genotyping circulating mononuclear cells from 263 patients with pancreatic ductal adenocarcinoma (PDAC), using 271 healthy volunteers as controls. As a result, both SNPs were more frequent in PDAC patients than in healthy volunteers (C1772T: 21 vs. 11%, p < 0.01; G1790A: 25 vs. 8%, p < 0.01). Further, both SNPs were associated with higher risks for PDAC (C1772T: OR=2.156, 95% CI: 1.324-3.511, p < 0.05; G1790A: OR=3.716, 95% CI: 2.213-6.238, p < 0.01). We also stained HIF-1alpha by immunohistochemistry in 68 PDAC tumors to examine their HIF-1alpha expression levels. To this end, we designed a semi-quantitative method that was based on the staining intensity and frequency of HIF-1alpha-positive cells. As a result, the G1790A SNP, but not C1772T SNP, was associated with an increased HIF-1alpha expression. We also related genotyping data to patient's survival times, serum CA19-9, and tumor's volumes, grades, stages and lymph-node metastasis. The C1772T SNP was not associated with any of these parameters. In contrast, the G1790A SNP was associated with increases in serum CA19-9 and in tumor volumes. In conclusion, the C1772T and G1790A SNPs in the HIF-1alpha gene increase the susceptibility to pancreatic cancer. In addition, the G1790A SNP is associated with increases in tumor-produced HIF-1alpha and in the progression of the cancer.