title: Polymorphisms in the hypoxia-inducible factor-1α gene confer susceptibility to pancreatic cancer.
abstract: The transcription factor hypoxia-inducible factor-1 (HIF-1) has α and β subunits. Recent studies have shown that the HIF-1α gene may have C1772T and G1790A single nucleotide polymorphisms (SNPs). These SNPs may increase the stability and activity of HIF-1α. 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-1α by immunohistochemistry in 68 PDAC tumors to examine their HIF-1α expression levels. To this end, we designed a semi-quantitative method that was based on the staining intensity and frequency of HIF-1α-positive cells. As a result, the G1790A SNP, but not C1772T SNP, was associated with an increased HIF-1α 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-1α gene increase the susceptibility to pancreatic cancer. In addition, the G1790A SNP is associated with increases in tumor-produced HIF-1α and in the progression of the cancer.
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Xiuchao
authors.initials: X
authors.lastname: Wang
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Liu
authors.forename: He
authors.initials: H
authors.lastname: Ren
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Yuan
authors.forename: Shasha
authors.initials: S
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Sheng
authors.forename: Tiansuo
authors.initials: T
authors.lastname: Zhao
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Fenghua
authors.initials: F
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Jihui
authors.initials: J
authors.lastname: Hao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018395:CA-19-9 Antigen / Q000097:blood; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D018395:CA-19-9 Antigen; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit