Methylated DNA in Pancreatic Juice Distinguishes Patients With Pancreatic Cancer From Controls

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 ma...

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Bibliographic Details
Published in:	Clinical gastroenterology and hepatology Vol. 18; no. 3; pp. 676 - 683.e3
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-03-2020
Subjects:	Chemistry Neoplasm Prognostic Secretin Neoplasm Chemistry GI PDAC HGD QuART MDM LGD Secretin IPMN Prognostic AUC
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 S. Chari: Study concept and design; critical review of manuscript for important intellectual content M. Wallace: Acquisition of clinical samples; critical review of manuscript for important intellectual content D. Ahlquist: Study concept and design; analysis and interpretation of data; critical review of the manuscript for important intellectual content; obtained funding; study supervision M. Levy: Acquisition of clinical samples; critical review of manuscript for important intellectual content T. Woodward: Acquisition of clinical samples; critical review of manuscript for important intellectual content G. Petersen: Study concept and design; critical review of manuscript for important intellectual content J. Kisiel: Study concept and design; critical review of manuscript for important intellectual content; study supervision S. Majumder: Study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; study supervision P. Foote: Laboratory testing and interpretation of data X. Cao: Laboratory testing and interpretation of data B. Petersen: Acquisition of clinical samples; critical review of manuscript for important intellectual content W. Taylor: Study concept and design; laboratory testing, analysis and interpretation of data; drafting of the manuscript; critical review of the manuscript for important intellectual content Author Contributions T. Yab: Study concept and design; study supervision; laboratory testing, and interpretation of data; critical review of the manuscript for important intellectual content B. Abu Dayyeh: Acquisition of clinical samples; critical review of manuscript for important intellectual content F. Gleeson: Acquisition of clinical samples; critical review of manuscript for important intellectual content C. Wu: Laboratory testing and interpretation of data D. Faigel: Acquisition of clinical samples; critical review of manuscript for important intellectual content C. Berger: Laboratory testing and interpretation of data M. Topazian: Acquisition of clinical samples; critical review of manuscript for important intellectual content M. Devens: Clinical research coordination SS Vege: Study concept and design; critical review of manuscript for important intellectual content R. Pannala: Study concept and design; acquisition of clinical samples; critical review of manuscript for important intellectual content T. Smyrk: Advice on pathology interpretation; analysis and interpretation of data H. Allawi: Critical review of the manuscript for important intellectual content D. Mahoney: Study concept and design; formal statistical analysis; critical review of the manuscript for important intellectual content E. Rajan: Acquisition of clinical samples; critical review of manuscript for important intellectual content M. Raimondo: Study concept and design; acquisition of clinical samples; critical review of manuscript for important intellectual content G. Lidgard: Critical review of the manuscript for important intellectual content B. Dukek: Laboratory testing and interpretation of data C. Nguyen: Acquisition of clinical samples; critical review of manuscript for important intellectual content
ISSN:	1542-3565 1542-7714
DOI:	10.1016/j.cgh.2019.07.017