Premium
Association between ulcerative growth and hypoxia inducible factor‐1α polymorphisms in colorectal cancer patients
Author(s) -
Fransén Karin,
Fenech Matthew,
Fredrikson Mats,
Dabrosin Charlotta,
Söderkvist Peter
Publication year - 2006
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20209
Subject(s) - biology , allele , colorectal cancer , hypoxia inducible factors , restriction fragment length polymorphism , vascular endothelial growth factor , cancer research , medicine , immunohistochemistry , angiogenesis , mdm2 , hypoxia (environmental) , endocrinology , cancer , microbiology and biotechnology , gene , genetics , immunology , vegf receptors , genotype , chemistry , organic chemistry , oxygen
The hypoxia inducible factor‐1α (HIF‐1α) has been found to be involved in several different physiological mechanisms, such as blood‐vessel formation, apoptosis, and erythropoiesis. HIF‐1α is hydroxylated at normoxia and rapidly degraded via the von Hippel–Lindau (VHL)/ubiquitin‐proteasome degradation system to prevent angiogenesis. In a previous study, the C1772T (P582S) and the G1790A (A588T) polymorphisms were identified in the human HIF‐1α gene, which was shown to have a higher transactivating capability in vitro compared to the wild type allele. However, the role for these polymorphisms in vivo is still unclear. In the present investigation, we have therefore studied the role of the two polymorphic variants in the development of colorectal cancer (CRC) with PCR/RFLP (restriction fragment length polymorphism), single strand conformation analysis (SSCA), and immunohistochemistry (IHC). A significant higher‐risk was identified between patients heterozygous for the C1772T polymorphism and the more severe ulcerative growth pattern compared to homozygous C1772C wild type tumors (RR = 5.2; 95% CI 1.26–21.6; P = 0.006). This was also verified on the allelic level (RR = 6.5; 95% CI 1.58–26.8; P = 0.001). In addition, patients carrying one or more polymorphic alleles in either the HIF‐1α C1772T or the G1790A polymorphisms display significant higher risk for the development of ulcerative CRCs (RR = 4.17; 95% CI = 1.33–13.08; P = 0.004). These results suggest that the HIF‐1α polymorpisms are an important factor for development of a subset of ulcerative intestinal tumors. Future screening of the polymorphic HIF‐1α allele may therefore be of importance in the selection of treatment strategies of CRC. © 2006 Wiley‐Liss, Inc.