Vlachostergios Panagiotis J, Evmorfopoulos Konstantinos, Zachos Ioannis, Dimitropoulos Konstantinos, Thodou Eleni, Samara Maria, Tzortzis Vassilios, Giakountis Antonis
Department of Medical Oncology, IASO Thessalias General Hospital, 41500 Larissa, Greece.
Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
Genes (Basel). 2024 Dec 22;15(12):1649. doi: 10.3390/genes15121649.
BACKGROUND/OBJECTIVES: Testicular germ cell tumors (TGCT) are common in young adult men and have high cure rates. Conventional serum tumor markers and imaging are not able to differentiate between histologic subtypes of the disease, which portend different prognoses and require distinct therapeutic strategies. Micro-RNAs (miRNAs) are small non-coding transcripts involved in the post-transcriptional regulation of gene expression, which have emerged as promising biomarkers in a variety of tumors. This study aimed to assess the potential of differentially expressed miRNAs in differential diagnosis and prognostication among TGCT patients with various histologic subtypes.
Transcriptomic analysis of 134 patients from The Cancer Genome Atlas (TCGA)-TGCT database was conducted. miRNA differential expression analysis among seminomatous, embryonal carcinoma, mixed GCT, and teratoma was performed, followed by ROC curve analysis of the most significantly up- and downregulated miRNAs, respectively. Statistical associations of miRNA expression with AJCC stage were also investigated along with miRNA target network analysis and evaluation of miRNA detection in patients' fluids.
Upregulation of seven miRNAs (hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-200a, hsa-mir-200b, hsa-mir-203b, hsa-mir-375, hsa-mir-582) and downregulation of seven additional miRNAs (hsa-mir-105-1, hsa-mir-105-2, hsa-mir-4433a, hsa-mir-548x, hsa-mir-5708, hsa-mir-6715a, hsa-mir-767) were identified. miRNAs displayed a high sensitivity/specificity of 0.94/1.0 (AUC = 0.98) for the upregulated and 0.97/0.94 (AUC = 0.96) for the downregulated signature. Deregulated expression of these miRNAs was significantly associated with AJCC stage and distant organ metastasis ( < 0.001), overall supporting their prognostic strength. Both signatures were detectable in body fluids, particularly urine. miRNA target network analysis supported the functional role of these miRNAs in the regulation of cancer-related processes such as cell proliferation via deregulation of pivotal oncogenes.
These findings support the clinical value of two novel miRNA signatures in differential diagnosis and prognostic stratification of various histologic subtypes of TGCT, with potential treatment implications.
背景/目的：睾丸生殖细胞肿瘤（TGCT）在年轻成年男性中很常见，治愈率很高。传统的血清肿瘤标志物和影像学检查无法区分该疾病的组织学亚型，而这些亚型预示着不同的预后，需要不同的治疗策略。微小RNA（miRNA）是参与基因表达转录后调控的小型非编码转录本，已成为多种肿瘤中有前景的生物标志物。本研究旨在评估差异表达的miRNA在不同组织学亚型的TGCT患者的鉴别诊断和预后评估中的潜力。
对来自癌症基因组图谱（TCGA）-TGCT数据库的134例患者进行转录组分析。对精原细胞瘤、胚胎癌、混合性生殖细胞肿瘤和畸胎瘤进行miRNA差异表达分析，然后分别对上调和下调最显著的miRNA进行ROC曲线分析。还研究了miRNA表达与美国癌症联合委员会（AJCC）分期的统计学关联，以及miRNA靶标网络分析和患者体液中miRNA检测的评估。
鉴定出7种miRNA上调（hsa-mir-135a-1、hsa-mir-13a-2、hsa-mir-200a、hsa-mir-200b、hsa-mir-203b、hsa-mir-375、hsa-mir-582）和另外7种miRNA下调（hsa-mir-105-1、hsa-mir-105-2、hsa-mir-4433a、hsa-mir-548x、hsa-mir-5708、hsa-mir-6715a、hsa-mir-767）。上调的miRNA显示出0.94/1.0（AUC = ）的高灵敏度/特异性，下调的特征为0.97/0.94（AUC = 0.96）。这些miRNA的失调表达与AJCC分期和远处器官转移显著相关（<0.001），总体上支持它们的预后强度。两种特征在体液中均可检测到，尤其是尿液。miRNA靶标网络分析支持这些miRNA在通过关键癌基因的失调来调节细胞增殖等癌症相关过程中的功能作用。
这些发现支持了两种新的miRNA特征在TGCT不同组织学亚型的鉴别诊断和预后分层中的临床价值，并具有潜在的治疗意义。
