Majumder Shounak, Raimondo Massimo, Taylor William R, Yab Tracy C, Berger Calise K, Dukek Brian A, Cao Xiaoming, Foote Patrick H, Wu Chung Wah, Devens Mary E, Mahoney Douglas W, Smyrk Thomas C, Pannala Rahul, Chari Suresh T, Vege Santhi Swaroop, Topazian Mark D, Petersen Bret T, Levy Michael J, Rajan Elizabeth, Gleeson Ferga C, Abu Dayyeh Barham, Nguyen Cuong C, Faigel Douglas O, Woodward Timothy A, Wallace Michael B, Petersen Gloria, Allawi Hatim T, Lidgard Graham P, Kisiel John B, Ahlquist David A
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida.
Clin Gastroenterol Hepatol. 2020 Mar;18(3):676-683.e3. doi: 10.1016/j.cgh.2019.07.017. Epub 2019 Jul 16.
BACKGROUND & AIMS: Precursors of pancreatic cancer arise in the ductal epithelium; markers exfoliated into pancreatic juice might be used to detect high-grade dysplasia (HGD) and cancer. Specific methylated DNA sequences in pancreatic tissue have been associated with adenocarcinoma. We analyzed these methylated DNA markers (MDMs) in pancreatic juice samples from patients with pancreatic ductal adenocarcinomas (PDACs) or intraductal papillary mucinous neoplasms (IPMNs) with HGD (cases), and assessed their ability to discriminate these patients from individuals without dysplasia or with IPMNs with low-grade dysplasia (controls).
We obtained pancreatic juice samples from 38 patients (35 with biopsy-proven PDAC or pancreatic cystic lesions with invasive cancer and 3 with HGD) and 73 controls (32 with normal pancreas and 41 with benign disease), collected endoscopically from the duodenum after secretin administration from February 2015 through November 2016 at 3 medical centers. Samples were analyzed for the presence of 14 MDMs (in the genes NDRG4, BMP3, TBX15, C13orf18, PRKCB, CLEC11A, CD1D, ELMO1, IGF2BP1, RYR2, ADCY1, FER1L4, EMX1, and LRRC4), by quantitative allele-specific real-time target and signal amplification. We performed area under the receiver operating characteristic curve analyses to determine the ability of each marker, and panels of markers, to distinguish patients with HGD and cancer from controls. MDMs were combined to form a panel for detection using recursive partition trees.
We identified a group of 3 MDMs (at C13orf18, FER1L4, and BMP3) in pancreatic juice that distinguished cases from controls with an area under the receiver operating characteristic value of 0.90 (95% CI, 0.83-0.97). Using a specificity cut-off value of 86%, this group of MDMs distinguished patients with any stage of pancreatic cancer from controls with 83% sensitivity (95% CI, 66%-93%) and identified patients with stage I or II PDAC or IPMN with HGD with 80% sensitivity (95% CI, 56%-95%).
We identified a group of 3 MDMs in pancreatic juice that identify patients with pancreatic cancer with an area under the receiver operating characteristic value of 0.90, including patients with early stage disease or advanced precancer. These DNA methylation patterns might be included in algorithms for early detection of pancreatic cancer, especially in high-risk cohorts. Further optimization and clinical studies are needed.
胰腺癌的前体起源于导管上皮；脱落到胰液中的标志物可用于检测高级别异型增生（HGD）和癌症。胰腺组织中特定的甲基化DNA序列与腺癌相关。我们分析了来自胰腺导管腺癌（PDAC）或伴有HGD的导管内乳头状黏液性肿瘤（IPMN）患者（病例组）的胰液样本中的这些甲基化DNA标志物（MDM），并评估它们将这些患者与无发育异常或伴有低级别异型增生的IPMN患者（对照组）区分开来的能力。
我们从38例患者（35例经活检证实为PDAC或伴有浸润性癌的胰腺囊性病变患者以及3例伴有HGD的患者）和73例对照者（32例胰腺正常者和41例患有良性疾病者）获取胰液样本，于2015年2月至2016年11月在3个医疗中心通过在内镜下于十二指肠给予促胰液素后收集样本。通过定量等位基因特异性实时靶标和信号扩增分析样本中14种MDM（在NDRG4、BMP3、TBX15、C13orf18、PRKCB、CLEC11A、CD1D、ELMO1、IGF2BP1、RYR2、ADCY1、FER1L4、EMX1和LRRC4基因中）的存在情况。我们进行了受试者工作特征曲线下面积分析，以确定每个标志物以及标志物组合区分HGD和癌症患者与对照者的能力。使用递归划分树将MDM组合形成一个检测面板。
我们在胰液中鉴定出一组3种MDM（位于C13orf18、FER1L4和BMP3基因），其受试者工作特征值下面积为0.90（95%CI，0.83 - 0.97），可区分病例组与对照组。使用86%的特异性截止值，这组MDM区分任何阶段胰腺癌患者与对照组的灵敏度为83%（95%CI，66% - 93%），并以80%的灵敏度（95%CI，56% - 95%）鉴定出I期或II期PDAC或伴有HGD的IPMN患者。
我们在胰液中鉴定出一组3种MDM，其受试者工作特征值下面积为0.90，可识别胰腺癌患者，包括早期疾病或癌前病变晚期患者。这些DNA甲基化模式可能纳入胰腺癌早期检测算法中，尤其是在高危人群中。需要进一步优化和进行临床研究。
