eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: final results of the ePHAS study
eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: final results of the ePHAS study
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DOI：
10.18632/oncotarget.8569
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发表时间：
2016-05-10
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通讯作者：
Frassineti, Giovanni Luca
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作者：
Gardini, Andrea Casadei;Marisi, Giorgia;Frassineti, Giovanni Luca
索拉非尼可能通过抑制血管内皮生长因子受体（VEGF-R）降低内皮型一氧化氮合酶（eNOS）活性，导致一氧化氮生成减少。在意大利的多中心ePHAS （eNOS多态性在HCC和索拉非尼）研究中，我们分析了eNOS多态性在接受索拉非尼治疗的肝细胞癌（HCC）患者的临床预后中的作用。我们的回顾性研究包括41例HCC患者的培训队列和87例HCC患者的验证队列，均接受索拉非尼治疗。通过直接测序或Real Time PCR分析三个eNOS多态性（eNOS -786T>C、eNOS VNTR 27bp 4a/b和eNOS+ 894G>T）与无进展生存期（PFS）和总生存期（OS）的关系（log-rank检验）。在单因素分析中，训练队列中纯合子为eNOS单倍型（HT1: T-4b在eNOS-786/eNOS VNTR）的患者的中位PFS （2.6 vs. 5.8个月，P < 0.0001）和OS （3.2 vs. 14.6个月，P = 0.024）低于其他单倍型患者。在验证集中，HT1纯合子患者的中位PFS （2.0 vs. 6.7个月，P < 0.0001）和OS （6.4 vs. 18.0个月，P < 0.0001）低于其他单倍型患者。多变量分析证实该单倍型是唯一独立的预后因素。我们的研究结果表明，eNOS基因中的单倍型HT1可能能够识别对索拉非尼耐药的HCC患者亚群。
Sorafenib may reduce endothelial nitric oxide synthase (eNOS) activity by inhibiting vascular endothelial growth factor receptors (VEGF-R), leading to a decrease in nitric oxide production. In the Italian multicenter ePHAS (eNOS polymorphisms in HCC and sorafenib) study, we analyzed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Our retrospective study included a training cohort of 41 HCC patients and a validation cohort of 87 HCC patients, all undergoing sorafenib treatment. Three eNOS polymorphisms (eNOS -786T>C, eNOS VNTR 27bp 4a/b and eNOS+ 894G>T) were analyzed by direct sequencing or Real Time PCR in relation to progressionfree survival (PFS) and overall survival (OS) (log-rank test). In univariate analysis, training cohort patients homozygous for eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, P < 0.0001) and OS (3.2 vs. 14.6 months, P = 0.024) than those with other haplotypes. In the validation set, patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, P < 0.0001) and OS (6.4 vs. 18.0 months, P < 0.0001) than those with other haplotypes. Multivariate analysis confirmed this haplotype as the only independent prognostic factor. Our results suggest that haplotype HT1 in the eNOS gene may be capable of identifying a subset of HCC patients who are resistant to sorafenib.