HOXA4/HOXB3 gene expression signature as a biomarker of recurrence in patients with high-grade serous ovarian cancer following primary cytoreductive surgery and first-line adjuvant chemotherapy
HOXA4/HOXB3 gene expression signature as a biomarker of recurrence in patients with high-grade serous ovarian cancer following primary cytoreductive surgery and first-line adjuvant chemotherapy
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DOI：
10.1016/j.ygyno.2018.01.022
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发表时间：
2018-04-01
影响因子：
4.7
通讯作者：
Ganapathi, Mahrukh K.
中科院分区：
文献类型：
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作者：
Miller, Katherine R.;Patel, Jai N.;Ganapathi, Mahrukh K.
目标.高级别浆液性卵巢癌（HGSOC）中有异常同源异型盒（HOX）基因表达的报道，但其预后意义尚不清楚。在具有RNA测序数据的原发性HGSOC样品的发现队列中与无进展生存期（PFS）相关的HOX基因，以及先前报道与临床结果相关的HOX基因，被选择用于原发性HGSOC样品的独立训练队列中的qPCR测试（n = 71）。使用单变量和多变量考克斯回归开发PFS的预后模型。患者被分层为风险组，以优化检验统计量。该模型在来自癌症基因组图谱（TCGA）的独立HGSOC队列中进行测试（n = 320）。在体外检测所选HOX基因对药物敏感性和活性氧（ROS）积累的影响。在多变量分析中，在训练队列中检测的23个HOX基因中，HOXA 4（HR = 120，95%CI = 1.07-134，P = 0.002）和HOXB 3（HR = 1.09，95%CI = 1.01-1.17，P = 0.027）过表达与较短的PFS显著相关。基于HOXA 4/HOXB 3风险评分的最佳截止值，高风险评分和低风险评分患者的中位PFS分别为16.9个月（95% CI = 14.6-21.2个月）和未达到（>80个月）（HR = 8.89，95% CI = 2.09-37.74，P < 0.001）。在TCGA中，HOXA 4/HOXB 3风险评分与无病生存率显著相关（HR = 1.44，95%CI = 1.00-2.09，P = 0.048）。HOXA 4或HOXB 3过表达可降低卵巢癌细胞对顺铂的敏感性，减少顺铂诱导的ROS产生（P <0. 05）。基于HOXA 4/HOXB 3基因表达的风险评分可能有助于预后风险分层，并在HGSOC患者中进行前瞻性验证。(C)2018爱思唯尔公司版权所有，保留所有权利。
Objectives. Aberrant homeobox (HOX) gene expression is reported in high-grade serous ovarian carcinoma (HGSOC), however, its prognostic significance remains unclear.Methods. HOX genes associated with progression-free survival (PFS) in a discovery cohort of primary HGSOC samples with RNA sequencing data, and those previously reported to be associated with clinical outcomes, were selected for qPCR testing in an independent training cohort of primary HGSOC samples (n = 71). A prognostic model for PFS was developed using univariate and multivariate Cox regression. Patients were stratified into risk groups that optimized the test statistic. The model was tested in an independent HGSOC cohort from The Cancer Genome Atlas (TCGA) (n = 320). The effect of selected HOX genes on drug sensitivity and reactive oxygen species (ROS) accumulation was examined in vitro.Results. Of 23 HOX genes tested in the training cohort, HOXA4 (HR = 120, 95% CI = 1.07-134, P = 0.002) and HOXB3 (HR = 1.09, 95% CI = 1.01-1.17, P = 0.027) overexpression were significantly associated with shorter PFS in multivariate analysis. Based on the optimal cutoff of the HOXA4/HOXB3 risk score, median PFS was 16.9 months (95% CI = 14.6-21.2 months) and not reached (>80 months) for patients with high and low risk scores, respectively (HR = 8.89, 95% CI = 2.09-37.74, P < 0.001). In TCGA, the HOXA4/HOXB3 risk score was significantly associated with disease-free survival (HR = 1.44, 95% CI = 1.00-2.09, P = 0.048). HOXA4 or HOXB3 overexpression in ovarian cancer cells decreased sensitivity to cisplatin and attenuated the generation of cisplatin-induced ROS (P < 0.05).Conclusions. HOXA4/HOXB3 gene expression-based risk score may be useful for prognostic risk stratification and warrants prospective validation in HGSOC patients. (C) 2018 Elsevier Inc. All, rights reserved.