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

Author:

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

Abstract

ObjectivePancreatic 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.DesignTo 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.ResultsComparative 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).ConclusionA combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.

Funder

NIH

DON Foundation

Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine

Khalifa Bin Zayed Foundation

the Robert M. and Marilyn Sternberg Family Charitable Foundation, the Helmsley Charitable Trust

NIH/NCI

the Hale Family Center for Pancreatic Cancer Research, Lustgarten Foundation

The Israel Science Foundation

NCI

Entertainment Industry Foundation

Lustgarten Foundation

NCI Early Detection Research Network

Pancreatic Cancer Action Network

American Association for Cancer Research

Dedicated Laboratory

Broman Family Fund for Pancreatic Cancer Research

Publisher

BMJ

Subject

Gastroenterology

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