Department of Anatomical Pathology, A.C. Camargo Cancer Center, São Paulo 01509‑010, Brazil.
NeoGene Laboratory, A.C. Camargo Cancer Center, São Paulo 01509‑010, Brazil.
Oncol Rep. 2019 Apr;41(4):2254-2264. doi: 10.3892/or.2019.6984. Epub 2019 Jan 28.
To identify biomarkers that could predict response or lack of response to conventional chemotherapy at the time of diagnosis of high‑grade serous ovarian carcinoma (HGSOC), the present study compared large‑scale gene expression from patients with short or long disease‑free survival times, according to the last cycle of chemotherapy, and validated these findings using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and conventional immunohistochemical (IHC) analysis. Samples were selected for microarray evaluation, at the time of diagnosis, using the following criteria: Identical debulking primary surgery, International Federation of Gynaecology and Obstetrics staging, histological subtype and grade. These were divided into 2 groups, regarding the outcome after 2 years of follow-up. Prostaglandin D2 synthase 21 kDa (brain) (PTGDS) was found to be expressed at a significantly higher level in the tumours of patients with a short disease‑free survival time, and this was validated by RT‑qPCR in all samples. Furthermore, the study evaluated PGD2, the protein product of the PTGDS gene, in a large cohort of 114 HGSOC patients using the Ventana Benchmark automated platform, and IHC positivity was correlated with clinicopathological data and outcome. The global gene expression analysis identified 1,149 genes that were differentially expressed in microarray data, according to the patient outcome. Further analysis RT‑qPCR validated PTGDS gene expression in the same samples (r=0.945; P<0.001). IHC analysis showed an inverse profile, with positivity for PGD2 strongly associated with an increase in disease‑free survival (P=0.009), the absence of relapse (P=0.039) and sensitivity to platinum‑based therapy (P=0.016). Multiple Cox regression showed that IHC evaluation of PGD2 was also a prognostic marker associated with relapse (hazard ratio, 0.37; P=0.002). Overall, the results showed that IHC evaluation of PGD2 is an independent marker of good prognosis in HGSOC. This finding contributes to our understanding of the mechanism of tumour regulation and to investigations into biomarkers that predict response to chemotherapy.
为了在高级别浆液性卵巢癌（HGSOC）诊断时鉴定出可预测对常规化疗的反应或无反应的生物标志物，本研究比较了根据最后一个化疗周期，疾病无进展生存时间较短或较长的患者的大规模基因表达，并使用逆转录-定量聚合酶链反应（RT-qPCR）和常规免疫组织化学（IHC）分析验证了这些发现。使用以下标准选择用于微阵列评估的样本：相同的减瘤性主要手术、国际妇产科联合会分期、组织学亚型和分级。这些样本根据 2 年随访后的结果分为 2 组。发现前列腺素 D2 合酶 21 kDa（脑）（PTGDS）在疾病无进展生存时间较短的患者肿瘤中表达水平明显更高，这在所有样本中通过 RT-qPCR 得到验证。此外，该研究使用 Ventana Benchmark 自动化平台在 114 名 HGSOC 患者的大队列中评估了 PGDS 基因的蛋白产物 PGD2，并将 IHC 阳性与临床病理数据和结果相关联。根据患者的结果，对微阵列数据进行了全局基因表达分析，鉴定出 1149 个差异表达的基因。进一步的 RT-qPCR 分析验证了相同样本中 PTGDS 基因的表达（r=0.945；P<0.001）。IHC 分析显示出相反的模式，PGD2 阳性与疾病无进展生存率增加（P=0.009）、无复发（P=0.039）和对铂类为基础的治疗敏感（P=0.016）强烈相关。多 Cox 回归显示，PGD2 的 IHC 评估也是与复发相关的预后标志物（危险比，0.37；P=0.002）。总的来说，结果表明，PGD2 的 IHC 评估是 HGSOC 中良好预后的独立标志物。这一发现有助于我们了解肿瘤调节的机制，并探索预测化疗反应的生物标志物。
