Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer

Roni Ben-Ami, Qiao Li Wang, Jinming Zhang, Julianna G. Supplee, Johannes F. Fahrmann, Roni Lehmann-Werman, Lauren K. Brais, Jonathan Nowak, Chen Yuan, Maureen Loftus, Ana Babic, Ehsan Irajizad, Tal Davidi, Aviad Zick, Ayala Hubert, Daniel Neiman, Sheina Piyanzin, Ofer Gal-Rosenberg, Amit Horn, Ruth ShemerBenjamin Glaser, Natalia Boos, Kunal Jajoo, Linda Lee, Thomas E. Clancy, Douglas A. Rubinson, Kimmie Ng, John A. Chabot, Fay Kastrinos, Michael Kluger, Andrew J. Aguirre, Pasi A. Jänne, Nabeel Bardeesy, Ben Stanger, Mark H. O’Hara, Jacob Till, Anirban Maitra, Erica L. Carpenter, Andrea J. Bullock, Jeanine Genkinger, Samir M. Hanash, Cloud P. Paweletz, Yuval Dor*, Brian M. Wolpin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Objective Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed. Design To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites. Results Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92). Conclusion A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.

Original languageAmerican English
Pages (from-to)639-648
Number of pages10
JournalGut
Volume73
Issue number4
DOIs
StatePublished - 7 Mar 2024

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