Identification of hypoxia‐inducible factor‐1α (HIF‐1α) polymorphism as a mutation in prostate cancer that prevents normoxia‐induced degradation

Abstract

The P582S HIF-1alpha is a stable variant and HIF-1alpha mutation is a mechanism for enhancing HIF-1alpha activity in human cancer. The recent identification of the identical P582S HIF-1alpha as a polymorphism suggests that this variant may increase tumor susceptibility or cause more aggressive biological behavior.

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

“…A recently published meta-analysis suggests that both the T allele and TT genotype were significantly associated with increased cancer risk [17]. Experimental data also support a functional role for the C-by-T substitution at the allele and homozygous genotype level [12,28,29]. We found that additivity was better fitted for metastasis but not to ADT resistance, even though the low number of patients carrying the TT genotype in metastasis analyses yielded a very wide CI, hence deserving careful interpretation.…”

“…Concordantly, two large case-control studies from the United States of America and China also observed no risk for having PCa in carriers of this polymorphism [19,26], even though opposite results have been also reported [16,27]. The C-by-T substitution in the +1772 locus at the oxygen-dependent domain of the HIF1A gene results in a proline-to-serine substitution and was shown to stabilise HIF1A and enhance its activity as a transcription factor in both normoxia and hypoxia [12,28]. In agreement, albeit we hypothesised those carriers of T allele were more susceptible to have cancer, our data, together with other, suggest no influence in earlier stages of prostate cancer development.…”

“…patients using univariate analysis. Another study observed a somatic rare mutation at the same locus in 1/15 androgen-independent prostate tumours, whereas functional studies demonstrated in androgen-independent prostate cancer cells that the T-allele is associated with increased transcriptional activity and protein expression [28]. Therefore, we hypothesise that carrying the T-allele, which stabilises HIF1a protein and upregulates the HIF1A1 gene expression, may offer a selective advantage to androgen-independent tumour cells through the upregulation of several genes involved in metastasis, angiogenesis, epithelial-to-mesenchymal transition or in other cancer-associated mechanisms [10,23,[31][32][33].…”

Single nucleotide polymorphisms in the HIF-1α gene and chemoradiotherapy of locally advanced rectal cancer

“…The investigated SNPs were selected as potentially clinically relevant polymorphisms based on previous studies (18)(19)(20)(21)(26)(27)(28). Genomic DNA was purified from whole blood using the NucloeSpin ® Tissue method according to the manufacturer's instructions (NucleoSpin Tissue, Macherey-Nagel, Germany; Feb 2001/Rev.…”

Oxygen Sensing: Recent Insights from Idiopathic Erythrocytosis

“…44 However, the P582S polymorphism has been found to be associated with other disease phenotypes, including decreased coronary artery collateralization in ischemic heart disease patients, lower exercise-induced oxygen consumption in patients age 60 and older, prostate carcinoma, head and neck cancer and type 2 diabetes. [45][46][47][48][49][50] …”