Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Neuroendocrinology, Neuromed Institute, IRCCS, Pozzilli, Italy.
J Transl Med. 2023 Aug 16;21(1):548. doi: 10.1186/s12967-023-04417-8.
Neuroendocrine tumors (NETs) early diagnosis is a clinical challenge that require a deep understanding of molecular and genetic features of this heterogeneous group of neoplasms. However, few biomarkers exist to aid diagnosis and to predict prognosis and treatment response. In the oncological field, tumor-educated platelets (TEPs) have been implicated as central players in the systemic and local responses to tumor growth, thereby altering tumor specific RNA profile. Although TEPs have been found to be enriched in RNAs, few studies have investigated the potential of a type of RNA, circular RNAs (circRNA), as platelet-derived biomarkers for cancer. In this proof-of-concept study, we aim to demonstrate whether the circRNAs signature of tumor educated platelets can be used as a liquid biopsy biomarker for the detection of gastroenteropancreatic (GEP)-NETs and the prediction of the early response to treatment.
We performed a 24-months, prospective proof-of-concept study in men and women with histologically proven well-differentiated G1-G2 GEP-NET, aged 18-80 years, naïve to treatment. We performed a RNAseq analysis of circRNAs obtained from TEPs samples of 10 GEP-NETs patients at baseline and after 3 months from therapy (somatostatin analogs or surgery) and from 5 patients affected by non-malignant endocrinological diseases enrolled as a control group.
Statistical analysis based on p < 0.05 resulted in the identification of 252 circRNAs differentially expressed between GEP-NET and controls of which 109 were up-regulated and 143 were down-regulated in NET patients. Further analysis based on an FDR value ≤ 0.05 resulted in the selection of 5 circRNAs all highly significant downregulated. The same analysis on GEP-NETs at baseline and after therapy in 5 patients revealed an average of 4983 remarkably differentially expressed circRNAs between follow-up and baseline samples of which 2648 up-regulated and 2334 down-regulated, respectively. Applying p ≤ 0.05 and FDR ≤ 0.05 filters, only 3/5 comparisons gave statistically significant results.
Our findings identified for the first time a circRNAs signature from TEPs as potential diagnostic and predictive biomarkers for GEP-NETs.
神经内分泌肿瘤（NETs）的早期诊断是一个临床挑战，需要深入了解这种异质性肿瘤群体的分子和遗传特征。然而，目前很少有生物标志物可用于辅助诊断，预测预后和治疗反应。在肿瘤学领域，肿瘤诱导的血小板（TEP）已被认为是肿瘤生长的全身和局部反应的核心参与者，从而改变了肿瘤特异性 RNA 谱。尽管已经发现 TEP 富含 RNA，但很少有研究探讨一种 RNA，即环状 RNA（circRNA）作为血小板衍生的癌症生物标志物的潜力。在这项概念验证研究中，我们旨在证明肿瘤诱导的血小板的 circRNA 特征是否可用作检测胃肠胰腺（GEP）-NET 和预测早期治疗反应的液体活检生物标志物。
我们对 10 名经组织学证实的分化良好的 G1-G2 GEP-NET 男性和女性进行了为期 24 个月的前瞻性概念验证研究，年龄在 18-80 岁之间，未经治疗。我们对基线时和治疗 3 个月后（生长抑素类似物或手术）来自 10 名 GEP-NET 患者的 TEP 样本以及来自 5 名患有非恶性内分泌疾病的患者的 TEPs 样本进行了 circRNA 的 RNAseq 分析，这些患者被作为对照组。
基于 p < 0.05 的统计分析结果鉴定出 252 个在 GEP-NET 和对照组之间差异表达的 circRNAs，其中 109 个在 NET 患者中上调，143 个下调。基于 FDR 值≤0.05 的进一步分析选择了 5 个高度显著下调的 circRNAs。对 5 名患者基线和治疗后的 GEP-NETs 进行相同的分析显示，在随访和基线样本之间有平均 4983 个显著差异表达的 circRNAs，分别有 2648 个上调和 2334 个下调。应用 p ≤ 0.05 和 FDR ≤ 0.05 过滤器，只有 3/5 次比较得出了统计学上显著的结果。
我们的研究结果首次发现 TEP 的 circRNAs 特征可作为 GEP-NET 的潜在诊断和预测生物标志物。
