Urology Department, Sto António Hospital, Porto Hospital Centre, Porto, Portugal; ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
Molecular Oncology Group-CI, Portuguese Institute of Oncology, Porto, Portugal; Genetics Laboratory, Faculty of Medicine, University of Lisbon, Lisboa, Portugal; LPCC - Portuguese League Against Cancer (NRNorte), Porto, Portugal; Instituto Rocha Cabral, Lisboa, Portugal.
Eur J Cancer. 2014 Jan;50(2):359-65. doi: 10.1016/j.ejca.2013.09.001. Epub 2013 Sep 30.
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.
缺氧诱导因子 1 阿尔法（HIF1a）是肿瘤细胞对缺氧反应的关键调节因子，协调了已知参与癌症侵袭性和转移行为的机制。在这项研究中，我们试图评估 HIF1A 中的一个功能遗传多态性与总体和转移性前列腺癌（PCa）风险以及对雄激素剥夺治疗（ADT）的反应之间的关联。使用来自外周血的 DNA，通过实时 PCR 对 1490 名男性受试者（754 名患有前列腺癌和 736 名无癌症对照）进行 HIF1A +1772 C>T（rs11549465）多态性基因分型。对符合雄激素剥夺治疗条件的癌症患者进行了巢式研究。使用单变量和多变量模型分析了对激素治疗的反应以及发生远处转移的风险。计算了年龄调整后的比值比以评估前列腺癌的风险。我们的结果表明，接受 ADT 的患者携带 HIF1A +1772 T 等位基因，发生远处转移的风险增加（OR，2.0；95%CI，1.1-3.9），并且在多变量分析后独立地对 ADT 耐药的风险增加了 6 倍（OR，6.0；95%CI，2.2-16.8）。该多态性与诊断为前列腺癌的风险增加无关（OR，0.9；95%CI，0.7-1.2）。HIF1A +1772 遗传多态性预测前列腺癌的侵袭性更强，支持 HIF1a 参与前列腺癌的生物学进展和 ADT 耐药性。使用缺氧标志物的分子谱可能有助于预测临床上相关的前列腺癌和对 ADT 的反应。
