Engels Megan M L, Berger Calise K, Mahoney Douglas W, Hoogenboom Sanne A, Sarwal Dhruv, Klatte Derk C F, De La Fuente Jaime, Gandhi Sonal, Taylor William R, Foote Patrick H, Doering Karen A, Delgado Adriana M, Burger Kelli N, Abu Dayyeh Barham K, Bofill-Garcia Aliana, Brahmbhatt Bhaumik, Chandrasekhara Vinay, Gleeson Ferga C, Gomez Victoria, Kumbhari Vivek, Law Ryan J, Lukens Frank J, Raimondo Massimo, Rajan Elizabeth, Storm Andrew C, Vargas Valls Eric J, van Hooft Jeanin E, Wallace Michael B, Kisiel John B, Majumder Shounak
Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida; Division of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
Clin Gastroenterol Hepatol. 2025 Apr;23(5):766-775. doi: 10.1016/j.cgh.2024.07.048. Epub 2024 Oct 28.
In previous studies, methylated DNA markers (MDMs) have been identified in pancreatic juice (PJ) for detecting pancreatic ductal adenocarcinoma (PDAC). In this prospective multicenter study, the sensitivity and specificity characteristics of this panel of PJ-MDMs was evaluated standalone and in combination with plasma carbohydrate antigen 19-9 (CA 19-9).
Paired PJ and plasma were assayed from 88 biopsy-proven treatment-naïve PDAC cases and 134 controls (53 with normal pancreas, 23 with chronic pancreatitis [CP], 58 with intraductal papillary mucinous neoplasm). Bisulfite-converted DNA from buffered PJ was analyzed using long-probe quantitative amplified signal assay targeting 14 MDMs (NDRG4, BMP3, TBX15, C13orf18, PRKCB, CLEC11A, CD1D, ELMO1, IGF2BP1, RYR2, ADCY1, FER1L4, EMX1, and LRRC4) and a reference gene (methylated B3GALT6). Logistic regression was used to fit the previously identified 3-MDM PJ panel (FER1L4, C13orf18, and BMP3). Discrimination accuracy was summarized using area under the receiver-operating characteristic curve (AUROC) with corresponding 95% confidence interval (CI).
Methylated FER1L4 had the highest individual AUROC of 0.83 (95% CI, 0.78-0.89). The AUROC for the 3-MDM PJ + plasma CA 19-9 model (0.95; 95% CI, 0.92-0.98) was higher than both the 3-MDM PJ panel (0.87; 95% CI, 0.82-0.92)) and plasma CA 19-9 alone (0.91; 95% CI, 0.87-0.96) (P = .0002 and .0135, respectively). At a specificity of 88% (95% CI, 81%-93%), the sensitivity of this model was 89% (95% CI, 80%-94%) for all PDAC stages and 83% (95% CI, 64%-94%) for stage I/II PDAC.
A panel combining PJ-MDMs and plasma CA 19-9 discriminates PDAC from both healthy and disease control groups with high accuracy. This provides support for combining PJ and blood-based biomarkers for enhancing diagnostic sensitivity and successful early PDAC detection.
在先前的研究中，已在胰液（PJ）中鉴定出甲基化DNA标志物（MDMs）用于检测胰腺导管腺癌（PDAC）。在这项前瞻性多中心研究中，对该组PJ-MDMs单独以及与血浆糖类抗原19-9（CA 19-9）联合使用时的敏感性和特异性特征进行了评估。
对88例经活检证实未经治疗的PDAC病例以及134例对照（53例胰腺正常、23例慢性胰腺炎[CP]、58例导管内乳头状黏液性肿瘤）的配对PJ和血浆进行检测。使用针对14种MDMs（NDRG4、BMP3、TBX15、C13orf18、PRKCB、CLEC11A、CD1D、ELMO1、IGF2BP1、RYR2、ADCY1、FER1L4、EMX1和LRRC4）以及一个参考基因（甲基化B3GALT6）的长探针定量扩增信号分析法，对来自缓冲PJ的亚硫酸氢盐转化DNA进行分析。采用逻辑回归分析来拟合先前鉴定出的3-MDM PJ组（FER1L4、C13orf18和BMP3）。使用受试者操作特征曲线下面积（AUROC）及其相应的95%置信区间（CI）来总结鉴别准确性。
甲基化FER1L4的个体AUROC最高，为0.83（95% CI，0.78 - 0.89）。3-MDM PJ + 血浆CA 19-9模型的AUROC（0.95；95% CI，0.92 - 0.98）高于3-MDM PJ组（0.87；95% CI，0.82 - 0.92）和单独的血浆CA 19-9（0.91；95% CI，0.87 - 0.96）（P分别为0.0002和0.0135）。在特异性为88%（95% CI，81% - 93%）时，该模型对所有PDAC分期的敏感性为89%（95% CI，80% - 94%），对I/II期PDAC的敏感性为83%（95% CI，64% - 94%）。
将PJ-MDMs与血浆CA 19-9相结合的检测组能高精度地区分PDAC与健康对照组和疾病对照组。这为联合使用PJ和基于血液的生物标志物以提高诊断敏感性及成功早期检测PDAC提供了支持。
