Zayakin Pawel, Sadovska Lilite, Eglītis Kristaps, Romanchikova Nadezhda, Radoviča-Spalviņa Ilze, Endzeliņš Edgars, Liepniece-Karele Inta, Eglītis Jānis, Linē Aija
Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, k-1, LV-1067 Riga, Latvia.
Latvian Oncology Center, Riga Eastern Clinical University Hospital, LV-1038 Riga, Latvia.
Cancers (Basel). 2023 Aug 30;15(17):4329. doi: 10.3390/cancers15174329.
Over the past decade, extracellular vesicles (EVs) have emerged as a promising source of cancer-derived RNAs for liquid biopsies. However, blood contains a pool of heterogeneous EVs released by a variety of cell types, making the identification of cancer RNA biomarkers challenging. Here, we performed deep sequencing of plasma EV RNA cargo in 32 patients with locally advanced breast cancer (BC) at diagnosis and 7 days after breast surgery and in 30 cancer-free healthy controls (HCs). To identify BC-derived RNA biomarkers, we searched for RNAs that had higher levels in BC EVs at the time of diagnosis compared with HCs and decreased after surgery. Data analysis showed that the fractions of miRNAs, snRNAs, snoRNAs, and tRFs were increased, but the fraction of lncRNAs was decreased in BC EVs as compared to HCs. BC-derived biomarker candidates were identified across various RNA biotypes. Considered individually, they had very high specificity but moderate sensitivity for the detection of BC, whereas a biomarker model composed of eight RNAs: SNORD3H, SNORD1C, SNORA74D, miR-224-5p, piR-32949, lnc-IFT-122-2, lnc-C9orf50-4, and lnc-FAM122C-3 was able to distinguish BC from HC EVs with an AUC of 0.902 (95% CI = 0.872-0.931, = 3.4 × 10) in leave-one-out cross-validation. Furthermore, a number of RNA biomarkers were correlated with the ER and HER2 expression and additional biomarker models were created to predict hormone receptor and HER2 status. Overall, this study demonstrated that the RNA composition of plasma EVs is altered in BC patients and that they contain cancer-derived RNA biomarkers that can be used for BC detection and monitoring using liquid biopsies.
在过去十年中，细胞外囊泡（EVs）已成为液体活检中癌症衍生RNA的一个有前景的来源。然而，血液中含有由多种细胞类型释放的异质性EVs池，这使得癌症RNA生物标志物的鉴定具有挑战性。在这里，我们对32例局部晚期乳腺癌（BC）患者在诊断时和乳腺手术后7天以及30名无癌健康对照（HCs）的血浆EV RNA货物进行了深度测序。为了鉴定BC衍生的RNA生物标志物，我们寻找了在诊断时BC EVs中水平高于HCs且术后降低的RNA。数据分析表明，与HCs相比，BC EVs中miRNA、snRNA、snoRNA和tRF的比例增加，但lncRNA的比例降低。在各种RNA生物类型中鉴定出了BC衍生的生物标志物候选物。单独考虑时，它们对BC的检测具有非常高的特异性但中等灵敏度，而由八个RNA组成的生物标志物模型：SNORD3H、SNORD1C、SNORA74D、miR-224-5p、piR-32949、lnc-IFT-122-2、lnc-C9orf50-4和lnc-FAM122C-3在留一法交叉验证中能够以0.902的AUC（95%CI = 0.872 - 0.931， = 3.4 × 10）区分BC和HC EVs。此外，一些RNA生物标志物与ER和HER2表达相关，并创建了额外的生物标志物模型来预测激素受体和HER2状态。总体而言，这项研究表明BC患者血浆EVs的RNA组成发生了改变，并且它们含有可用于通过液体活检进行BC检测和监测的癌症衍生RNA生物标志物。
