An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study.
An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study.
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DOI：
10.1053/j.gastro.2022.06.090
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发表时间：
2022-11
期刊：
影响因子：
29.4
通讯作者：
中科院分区：
文献类型：
--
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胰腺导管腺癌（PDAC）的发病率在世界范围内呈上升趋势，大多数患者在最初诊断时存在不可切除的疾病。碳水化合物抗原19-9 （CA19-9）水平的测定缺乏足够的敏感性和特异性，无法进行早期检测；因此，开发PDAC的替代分子诊断生物标志物的需求尚未得到满足。新出现的证据表明，肿瘤来源的外泌体货物，特别是mirna，为开发癌症特异性生物标志物提供了一个有吸引力的平台。本文对血液标本进行全基因组分析，以开发基于外泌体的转录组特征，用于无创和早期检测PDAC。在44例早期PDAC患者和57例非疾病对照中进行了小rna测序。使用机器学习算法，对一组无细胞（cf）和外泌体（exo） mirna进行优先排序，以区分PDAC患者和对照组。随后，使用实时荧光定量PCR （qRT-PCR）在独立队列（n=191）中训练和验证生物标志物的性能。测序分析最初确定了PDAC中30个过表达的mirna。随后，使用qRT-PCR分析，该小组减少到13个标记（5个cf-和8个exo- mirna），成功地识别了PDAC所有阶段的患者（AUC=0.98训练队列；AUC=0.93验证队列）；但更重要的是，对于早期PDAC的识别同样稳健（1期和ii期；AUC=0.93）。此外，这种转录组学特征成功地鉴定出CA19-9阴性病例（<37 U/ml； AUC=0.96），当与CA19-9水平联合分析时，显著提高了总体诊断准确性（AUC=0.99，而单独CA19-9的AUC=0.86）。在这项研究中，开发了一种基于外泌体的液体活检特征，用于无创和可靠的PDAC患者检测。我们基于外泌体的转录组特征结合了无细胞和外泌体microRNAs，有可能以高诊断准确性识别胰腺导管腺癌患者，并为这种致命恶性肿瘤的早期检测提供了重要的无创检测方法。
Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and majority of patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lack adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly miRNAs, offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC. Small RNA-sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 non-disease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs was prioritized that discriminated PDAC patients from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n=191) using quantitative real time PCR (qRT-PCR) assays. The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (AUC=0.98 training cohort; AUC=0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages 1&II; AUC=0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/ml; AUC=0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC=0.99 vs. AUC=0.86 for CA19-9 alone). In this study, an exosome-based liquid-biopsy signature for the noninvasive and robust detection of patients with PDAC was developed. Our exosome-based transcriptomic signature that combines cell-free and exosomal microRNAs has the potential to identify patients with pancreatic ductal adenocarcinoma with high diagnostic accuracy, and offers an important noninvasive assay for early detection of this fatal malignancy.
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