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

Autor:	Ben-Ami R; Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Wang QL; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden., Zhang J; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Supplee JG; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Fahrmann JF; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Lehmann-Werman R; Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Brais LK; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Nowak J; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA., Yuan C; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Loftus M; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Babic A; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Irajizad E; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Davidi T; Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel., Zick A; Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel., Hubert A; Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel., Neiman D; Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Piyanzin S; Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Gal-Rosenberg O; Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Horn A; Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Shemer R; Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Glaser B; Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.; Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel., Boos N; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Jajoo K; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Lee L; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Clancy TE; Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Rubinson DA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Ng K; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Chabot JA; Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA., Kastrinos F; Division of Digestive and Liver Diseases, Columbia University Irving Medical Cancer and the Vagelos College of Physicians and Surgeons, New York, New York, USA., Kluger M; Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA., Aguirre AJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Jänne PA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Bardeesy N; Massachusetts General Hospital Cancer Center, Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA., Stanger B; Department of Medicine, Division of Gastroenterology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA., O'Hara MH; Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Till J; Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Maitra A; Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA., Carpenter EL; Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Bullock AJ; Division of Hematology and Oncology, Beth-Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA., Genkinger J; Department of epidemiology, Mailman school of public health, Columbia university, New York, New York, USA.; Herbert Irving Comprehensive Cancer Center, Columbia university Irving Medical Center, New York, New York, USA., Hanash SM; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Paweletz CP; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Dor Y; Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel Brian_Wolpin@dfci.harvard.edu yuvald@ekmd.huji.ac.il., Wolpin BM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Brian_Wolpin@dfci.harvard.edu yuvald@ekmd.huji.ac.il.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2024 Mar 07; Vol. 73 (4), pp. 639-648. Date of Electronic Publication: 2024 Mar 07.
DOI:	10.1136/gutjnl-2023-331074
Abstrakt:	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. Competing Interests: Competing interests: ABu has received consulting fees from Exelixis and Geistlich Pharma. KM declares research funding from Celgene and Trovagene. AJA has consulted for Oncorus, Inc., Arrakis Therapeutics, and Merck & Co., Inc, and has research funding from Mirati Therapeutics, Syros, Deerfield, Inc., and Novo Ventures that is unrelated to this work. AM is listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection and serves as a consultant for Tezcat Biosciences. BG, RS and YD have filed patents on cfDNA analysis technology, and received research funding from GRAIL. BMW declares research funding from Celgene, Eli Lilly Novartis and Revolution Medicines, and consulting for Celgene, GRAIL, Ipsen and Mirati. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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