Polymorphism in the hypoxia-inducible factor 1α gene may confer susceptibility to androgen-independent prostate cancer

Abstract

The hypoxia-inducible factor 1alpha (HIF-1alpha) plays a major role in cancer progression. The role of this transcription factor in prostate cancer development and its transition to a metastatic and androgen refractory state remains to be elucidated. Previous reports have identified the existence of single nucleotide polymorphisms (SNPs) in the oxygen-dependent degradation domain of the HIF-1alpha gene in renal cell carcinoma, head and neck squamous cell carcinoma, and androgen-independent prostate cancer (AIPC). Studies in prostate cancer, however, are variable and limited in the number of cases assessed. Herein we further investigate these SNPs, specifically C1772T (which results in an amino acid change from proline 582 to serine) and G1790A (alanine 588 to threonine). The frequency of these polymorphisms was evaluated in a population of individuals with metastatic AIPC and compared to a set of healthy control subjects. The distribution of HIF-1alpha genotypes for C1772T in 196 AIPC patients was 161 C/C (82.1%), 29 C/T (14.8%), and 6 T/T (3.1%). The genotype distribution in 196 controls was 179 C/C (91.3%), 14 C/T (7.1%), and 3 T/T (1.5%). Our results demonstrate a significant difference in genotype distribution between AIPC patients and control subjects only for the C1772T polymorphism (p = 0.024). The association of the incidence of the polymorphism with overall survival was determined to be not statistically significant (p = 0.93) by the Mantel-Haenszel (log-rank) test. These results suggest that the C1772T polymorphism in HIF-1alpha may confer susceptibility to AIPC and contribute to the progression or metastasis of this disease.

Hypoxia-inducible factor-1α expression and gemcitabine chemotherapy for pancreatic cancer

“…In this study, the C1772T and G1790A mutation rates in pancreatic cancer were 10% (1/10) and 0%, respectively, for pancreatic cancer and 6.3% (1/16) and 6.3% (1/16), respectively, for gallbladder cancer (all heteromutation-type). These results, together with those of previous reports (2,(8)(9)(10)(11) show a low SNP rate for all cancers, except renal cancer, suggesting the lack of an association between SNPs and carcinogenesis.…”

“…However, type 2 diabetes mellitus is a risk factor for pancreatic cancer, which suggests an association between the development of pancreatic cancer and the SNPs of HIF-1α. There have been studies on an association between carcinogenesis and HIF-1α SNPs in cancer in various organs (2,(8)(9)(10)(11). The C1772T and G1790A mutation rates were reported to be 18 and 11%, respectively, in patients with head or neck cancer, and 11 and 8%, respectively, in healthy subjects, with no statistically significant differences between the 2 groups (2).…”

The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration

“…Concordantly, a recent study demonstrated that HIF1a expression contributed both to metastasis and chemo-resistance of castration resistant prostate cancer [30]. A study comparing HIF1A +1772 C>T genotypes between castration-resistant PCa and non-cancer men showed that the T-allele was overrepresented in the cancer group, although it was not associated with survival [18]. Noteworthy, this report presents data from 196 castration-resistant Table 3 Clinicopathological characteristics features of the group of patients under that received ADT (n = 429).…”

“…In prostate cancer, the few studies were conducted in distinct ethnic populations and clinicopathological characteristics leading to conflicting results [16,18,19]. Furthermore, the association of HIF1A +1772 C>T SNP with prostate cancer progression, metastasis and refractoriness to androgen deprivation therapy (ADT) merits further evaluation in larger series of patients.…”

Common polymorphisms in the HIF-1αgene confer susceptibility to digestive cancer: a meta-analysis

“…The HIF-1α gene has been mapped to locus 14q21-q24. Two common functional polymorphisms, C1772T (rs11549465 C>T) and G1790A (rs11549467 G>A), in the human HIF-1α gene that cause amino acid substitutions within the oxygen-dependent degradation domain may result in the overexpression of this protein and subsequent changes in the expression of downstream target genes, thus contributing to cancer development and progression (Chau et al, 2005). Several previous studies have suggested that HIF-1α C1772T and G1790A polymorphisms may play important roles in the risk of digestive cancer (Ling et al, 2005;Fransen et al, 2006;Li et al, 2009;Hsiao et al, 2010;Kang et al, 2011;Wang et al, 2011), while other studies found no convincing evidence of these polymorphisms in increasing susceptibility to digestive cancer (Kuwai et al, 2004;Knechtel et al, 2010).…”