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

作者：Fraga Avelino^*; Ribeiro Ricardo; Principe Paulo; Lobato Carlos; Pina Francisco; Mauricio Joaquina; Monteiro Catia; Sousa Hugo; Calais da Silva F; Lopes Carlos; Medeiros Rui

来源：European Journal of Cancer, 2014, 50(2): 359-365.

DOI：10.1016/j.ejca.2013.09.001

• Androgen deprivation therapy
• Hypoxia inducible factor 1 alpha
• Metastasis
• Prostate cancer
• Single nucleotide polymorphism

The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT).
The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk.
Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95% CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95% CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95% CI, 0.7-1.2).
The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

• 出版日期2014-1