全血中的 microRNA 标志物用于胰腺癌检测。

MicroRNA biomarkers in whole blood for detection of pancreatic cancer.

机构信息

Department of Oncology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark2Department of Medicine, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark3Department of Gastroenterology, Herlev Hospital, Copenhagen Universit.

Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.

出版信息

JAMA. 2014;311(4):392-404. doi: 10.1001/jama.2013.284664.

DOI:10.1001/jama.2013.284664

PMID:24449318

Abstract

IMPORTANCE

Biomarkers for the early diagnosis of patients with pancreatic cancer are needed to improve prognosis.

OBJECTIVES

To describe differences in microRNA expression in whole blood between patients with pancreatic cancer, chronic pancreatitis, and healthy participants and to identify panels of microRNAs for use in diagnosis of pancreatic cancer compared with the cancer antigen 19-9 (CA19-9).

DESIGN, SETTING, AND PARTICIPANTS: A case-control study that included 409 patients with pancreatic cancer and 25 with chronic pancreatitis who had been included prospectively in the Danish BIOPAC (Biomarkers in Patients with Pancreatic Cancer) study (July 2008-October 2012) plus 312 blood donors as healthy participants. The microRNA expressions in pretreatment whole blood RNA samples were collected and analyzed in 3 randomly determined subcohorts: discovery cohort (143 patients with pancreatic cancer, 18 patients with chronic pancreatitis, and 69 healthy participants), training cohort (180 patients with pancreatic cancer, 1 patient with chronic pancreatitis, and 199 healthy participants), and validation cohort (86 patients with pancreatic cancer, 7 patients with chronic pancreatitis, and 44 healthy participants); 754 microRNAs were screened in the discovery cohort and 38 microRNAs in the training cohort and 13 microRNAs in the validation cohort.

MAIN OUTCOMES AND MEASURES

Identification of microRNA panels (classifiers) for diagnosing pancreatic cancer.

RESULTS

The discovery cohort demonstrated that 38 microRNAs in whole blood were significantly dysregulated in patients with pancreatic cancer compared with controls. These microRNAs were tested in the training cohort and 2 diagnostic panels were constructed comprising 4 microRNAs in index I (miR-145, miR-150, miR-223, miR-636) and 10 in index II (miR-26b, miR-34a, miR-122, miR-126*, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p). The test characteristics for the training cohort were index I area under the curve (AUC) of 0.86 (95% CI, 0.82-0.90), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.64 (95% CI, 0.57-0.71); index II AUC of 0.93 (95% CI, 0.90-0.96), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.85 (95% CI, 0.80-0.85); and CA19-9 AUC of 0.90 (95% CI, 0.87-0.94), sensitivity of 0.86 (95% CI, 0.80-0.90), and specificity of 0.99 (95% CI, 0.96-1.00). Performances were strengthened in the validation cohort by combining panels and CA19-9 (index I AUC of 0.94 [95% CI, 0.90-0.98] and index II AUC of 0.93 [95% CI, 0.89-0.97]). Compared with CA19-9 alone, the AUC for the combination of index I and CA19-9 was significantly higher (P = .01). The performance of the panels in patients with stage IA-IIB pancreatic cancer was index I AUC of 0.80 (95% CI, 0.73-0.87); index I and CA19-9 AUC of 0.83 (95% CI, 0.76-0.90); index II AUC of 0.91 (95% CI, 0.87-0.94); and index II and CA19-9 AUC of 0.91 (95% CI, 0.86-0.95).

CONCLUSIONS AND RELEVANCE

This study identified 2 diagnostic panels based on microRNA expression in whole blood with the potential to distinguish patients with pancreatic cancer from healthy controls. Further research is necessary to understand whether these have clinical implications for early detection of pancreatic cancer and how much this information adds to serum CA19-9.

摘要

重要性：需要生物标志物来早期诊断胰腺癌患者，以改善预后。

目的：描述胰腺癌患者、慢性胰腺炎患者和健康参与者全血中 microRNA 表达的差异，并鉴定用于诊断胰腺癌的 microRNA 面板，与癌症抗原 19-9（CA19-9）相比。

设计、设置和参与者：一项病例对照研究，纳入了前瞻性纳入丹麦 BIOPAC（胰腺癌患者的生物标志物）研究的 409 例胰腺癌患者和 25 例慢性胰腺炎患者，以及 312 名健康献血者作为健康对照组。在 3 个随机确定的亚队列中采集并分析预处理全血 RNA 样本中的 microRNA 表达：发现队列（143 例胰腺癌患者、18 例慢性胰腺炎患者和 69 名健康参与者）、训练队列（180 例胰腺癌患者、1 例慢性胰腺炎患者和 199 名健康参与者）和验证队列（86 例胰腺癌患者、7 例慢性胰腺炎患者和 44 名健康参与者）；在发现队列中筛选了 754 个 microRNA，在训练队列中筛选了 38 个 microRNA，在验证队列中筛选了 13 个 microRNA。

主要结局和测量：鉴定用于诊断胰腺癌的 microRNA 面板（分类器）。

结果：发现队列显示，与对照组相比，胰腺癌患者全血中有 38 个 microRNA 明显失调。在训练队列中对这些 microRNA 进行了测试，并构建了两个诊断面板，分别包含指数 I（miR-145、miR-150、miR-223、miR-636）中的 4 个 microRNA 和指数 II（miR-26b、miR-34a、miR-122、miR-126*、miR-145、miR-150、miR-223、miR-505、miR-636、miR-885.5p）中的 10 个 microRNA。训练队列的测试特征为指数 I 的 AUC 为 0.86（95%CI，0.82-0.90），敏感性为 0.85（95%CI，0.79-0.90），特异性为 0.64（95%CI，0.57-0.71）；指数 II 的 AUC 为 0.93（95%CI，0.90-0.96），敏感性为 0.85（95%CI，0.79-0.90），特异性为 0.85（95%CI，0.80-0.85）；CA19-9 的 AUC 为 0.90（95%CI，0.87-0.94），敏感性为 0.86（95%CI，0.80-0.90），特异性为 0.99（95%CI，0.96-1.00）。在验证队列中，通过联合面板和 CA19-9 可以增强性能（指数 I 的 AUC 为 0.94（95%CI，0.90-0.98）和指数 II 的 AUC 为 0.93（95%CI，0.89-0.97））。与单独使用 CA19-9 相比，组合指数 I 和 CA19-9 的 AUC 显著更高（P =.01）。在 I 期至 IIB 期胰腺癌患者中，面板的表现为指数 I 的 AUC 为 0.80（95%CI，0.73-0.87）；指数 I 和 CA19-9 的 AUC 为 0.83（95%CI，0.76-0.90）；指数 II 的 AUC 为 0.91（95%CI，0.87-0.94）；指数 II 和 CA19-9 的 AUC 为 0.91（95%CI，0.86-0.95）。

结论和相关性：本研究基于全血 microRNA 表达鉴定了 2 个用于诊断胰腺癌的诊断面板，有可能将胰腺癌患者与健康对照组区分开来。需要进一步研究以了解这些面板是否对早期检测胰腺癌具有临床意义，以及这些信息对血清 CA19-9 有多少补充。