这项研究的目的是探索microRNAs(miRNAs)作为卵巢颗粒细胞肿瘤(GCTs)的改良标志物在癌症诊断和预后预测中的临床应用。目前的组织病理学和遗传标记,如FOXL2基因突变的存在来区分两种主要亚型并不完全准确,因此需要新的生物标志物.
五个福尔马林固定的miRNA表达谱,使用AffymetrixmiRNA3.0阵列评估石蜡包埋(FFPE)成人GCT和5个青少年GCT,并比较差异表达。通过定量RT-PCR在另外33个FFPE肿瘤和4个正常颗粒细胞样品中评估10个miRNA,它们的表达与临床信息相关。
MicroRNA阵列发现37个miRNAs在两种GCT亚型之间差异表达(p<0.05,倍数变化≥2,其中,miRs-138-5p,-184,-204-5p,-29c-3p,通过RT-qPCR验证-328-3p和-501-3p在两种GCT亚型之间差异表达(p<0.05)。此外,miR-184的表达可预测成人GCTs的肿瘤复发,特别适用于诊断为I期和II期以及仅I期疾病的患者(分别为p<0.001和p<0.05)。
这项研究首次报道了使用FFPE肿瘤样品的人卵巢GCT的全局miRNA表达谱。我们已经验证了6种miRNAs作为GCTs亚型分类的新标记,miR-138-5p水平低,与早期肿瘤阶段相关。低miR-184丰度与早期成人GCT患者的肿瘤复发相关,作为候选预测生物标志物。现在需要进一步的研究来证实这些miRNA作为诊断和复发标志物的临床效用。并了解它们在GCTs发病机制中的可能作用。
The aim of this study was to explore the clinical utility of microRNAs (miRNAs) as improved markers of ovarian granulosa cell tumours (GCTs) for cancer diagnosis and prognosis prediction. Current histopathological and genetic markers, such as the presence of a FOXL2 gene mutation to distinguish between the two major subtypes are not wholly accurate and as such novel biomarkers are warranted.
The miRNA expression profiles of five formalin-fixed, paraffin-embedded (FFPE) adult-GCTs and five juvenile-GCTs were assessed using Affymetrix miRNA 3.0 Arrays and compared for differential expression. Ten miRNAs were assessed in an additional 33 FFPE tumours and four normal granulosa cell samples by quantitative RT-PCR, and their expression correlated to clinical information.
MicroRNA array found 37 miRNAs as differentially expressed between the two GCT subtypes (p < 0.05, fold change ≥2 and among these, miRs -138-5p, -184, -204-5p, -29c-3p, -328-3p and -501-3p were validated by RT-qPCR as differentially expressed between the two GCT subtypes (p < 0.05). In addition, the expression of miR-184 was predictive of tumour recurrence in adult-GCTs, specifically for patients diagnosed with stage I and II and stage I only disease (p < 0.001 and p < 0.05, respectively).
This study is the first to report on global miRNA expression profiles of human ovarian GCTs using FFPE tumour samples. We have validated six miRNAs as novel markers for subtype classification in GCTs with low levels of miR-138-5p correlating with early tumour stage. Low miR-184 abundance was correlated with tumour recurrence in early stage adult-GCT patients as a candidate predictive biomarker. Further studies are now needed to confirm the clinical utility of these miRNAs as diagnostic and recurrence markers, and understand their possible roles in the pathogenesis of GCTs.