ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib
ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib
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DOI：
10.3390/cancers11071023
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发表时间：
2019-06-26
期刊：
影响因子：
5.2
通讯作者：
Casadei-Gardini, Andrea
中科院分区：
文献类型：
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作者：
Marisi, Giorgia;Petracci, Elisabetta;Casadei-Gardini, Andrea
索拉非尼代表了晚期肝细胞癌的治疗标准，尽管大量患者报告疗效有限。本研究旨在评价血管生成素-2(ANGPT2)和内皮源性一氧化氮合酶(NOS3)基因单核苷酸多态性在135例接受索拉非尼治疗的晚期肝癌患者中的预后价值。用直接测序法分析8个ANGPT2基因多态性与总生存期(OS)和无进展生存期(PFS)的关系。单因素分析显示，ANGPT2rs55633437和NOS3rs2070744与OS和PFS相关。尤其是ANGPT2rs55633437TT/GT纯合子携带者的中位OS(4.66个月比15.5个月，风险比(HR)4.86，95%可信区间2.73~8.67，p<；0.001)和PFS(1.58比6.27个月，HR 4.79，95%CI 2.73~8.35，p<；0.001)显著低于G等位基因纯合子。此外，与T等位基因纯合子相比，NOS3rs2070744 TC/CC纯合子患者的中位OS(15.6月比9.1月，HR 0.65，95%CI 0.44~0.97；p=0.036)和PFS(7.03月比3.5月，HR 0.43，95%CI 0.30~0.63；p<；0.001)显著高于T等位基因纯合子。多变量分析证实这些基因多态性是独立的预后因素。我们的结果提示，ANGPT2rs55633437和NOS3rs2070744基因多态可以确定肝癌患者中对索拉非尼更耐药的子集。
Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited efficacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 (ANGPT2) and endothelial-derived nitric oxide synthase (NOS3) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73-8.67, p < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73-8.35, p < 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44-0.97; p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30-0.63; p < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.