Inherited Determinants of Ovarian Cancer Survival
Inherited Determinants of Ovarian Cancer Survival
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DOI：
10.1158/1078-0432.ccr-09-2553
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发表时间：
2010-02-01
影响因子：
11.5
通讯作者：
Hartmann, Lynn C.
中科院分区：
文献类型：
--
作者：
Goode, Ellen L.;Maurer, Matthew J.;Hartmann, Lynn C.
目的：由于不同病例的预后不同，我们试图检查卵巢癌相关途径中227个候选基因的常见遗传变异是否与卵巢癌的总体生存率有关，这些途径包括血管生成、炎症、解毒、糖基化、一碳转移、细胞凋亡、细胞周期调节和细胞衰老。实验设计：采自1999年至2006年梅奥诊所确诊的325例侵袭性上皮性卵巢癌患者的血液样本。在中位数3.8年(0.1-8.6年)的随访中，观察到157例死亡。在1,416个单核苷酸多态(SNP)上对生殖系DNA进行分析。结果：血管生成的变异与总体(P=0.03)和浆液性癌患者(P=0.004)的生存时间密切相关，尤其是EIF2B5rs4912474(所有患者HR，0.69；95%CI，0.54-0.89；P=0.004)，VEGFC rs17697305(浆液性亚型HR，2.29；95%可信区间为1.34~3.92(P=0.003)，有4个SNPs在VHL中存在。炎症通路内的变异接近显著(ALL患者，P=0.09)，CCR3、IL1B、IL18、CCL2和ALOX5中与生存时间相关的SNPs值得追踪。结论：广泛的多途径评估发现，有证据表明遗传差异可能在卵巢癌患者的预后中起作用，特别是在血管生成和炎症通路中的基因。我们的工作支持以此类介体为目标的努力，以获得治疗收益。临床癌症资源；16(3)；995-1007。(C)2010年AACR。
Purpose: Due to variation of outcome among cases, we sought to examine whether overall survival in ovarian cancer was associated with common inherited variants in 227 candidate genes from ovarian cancer-related pathways including angiogenesis, inflammation, detoxification, glycosylation, one-carbon transfer, apoptosis, cell cycle regulation, and cellular senescence.Experimental Design: Blood samples were obtained from 325 women with invasive epithelial ovarian cancer diagnosed at the Mayo Clinic from 1999 to 2006. During a median follow-up of 3.8 years (range, 0.1-8.6 years), 157 deaths were observed. Germline DNA was analyzed at 1,416 single nucleotide polymorphisms (SNP). For all patients, and for 203 with serous subtype, we assessed the overall significance of each gene and pathway, and estimated risk of death via hazard ratios (HR) and 95% confidence intervals (CI), adjusting for known prognostic factors.Results: Variation within angiogenesis was most strongly associated with survival time overall (P = 0.03) and among patients with serous cancer (P = 0.05), particularly for EIF2B5 rs4912474 (all patients HR, 0.69; 95% CI, 0.54-0.89; P = 0.004), VEGFC rs17697305 (serous subtype HR, 2.29; 95% CI, 1.34-3.92; P = 0.003), and four SNPs in VHL. Variation within the inflammation pathway was borderline significant (all patients, P = 0.09), and SNPs in CCR3, IL1B, IL18, CCL2, and ALOX5 which correlated with survival time are worthy of follow-up.Conclusion: An extensive multiple-pathway assessment found evidence that inherited differences may play a role in outcome of ovarian cancer patients, particularly in genes within the angiogenesis and inflammation pathways. Our work supports efforts to target such mediators for therapeutic gain. Clin Cancer Res; 16(3); 995-1007. (C) 2010 AACR.