Digital PCR-based plasma cell-free DNA mutation analysis for early-stage pancreatic tumor diagnosis and surveillance
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ORIGINAL ARTICLE—LIVER, PANCREAS, AND BILIARY TRACT
Digital PCR-based plasma cell-free DNA mutation analysis for early-stage pancreatic tumor diagnosis and surveillance Tetsuhiro Okada1,2 • Yusuke Mizukami1,2 • Yusuke Ono1,2 • Hiroki Sato2 • Akihiro Hayashi2 • Hidemasa Kawabata2 • Kazuya Koizumi3 • Sakue Masuda3 • Shinichi Teshima4 • Kuniyuki Takahashi5 • Akio Katanuma5 • Yuko Omori6 • Hirotoshi Iwano7 • Masataka Yamada7 • Tomoki Yokochi8 • Shingo Asahara8 • Kazumichi Kawakubo9 • Masaki Kuwatani9 • Naoya Sakamoto9 • Katsuro Enomoto2 Takuma Goto2 • Junpei Sasajima1,2 • Mikihiro Fujiya2 • Jun Ueda10 • Seiji Matsumoto10 • Kenzui Taniue1 • Ayumu Sugitani1 • Hidenori Karasaki1 • Toshikatsu Okumura2
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Received: 20 April 2020 / Accepted: 17 August 2020 Ó Japanese Society of Gastroenterology 2020
Abstract Background Cell-free DNA (cfDNA) shed from tumors into the circulation offers a tool for cancer detection. Here, we evaluated the feasibility of cfDNA measurement and utility of digital PCR (dPCR)-based assays, which reduce subsampling error, for diagnosing pancreatic ductal adenocarcinoma (PDA) and surveillance of intraductal papillary mucinous neoplasm (IPMN). Methods We collected plasma from seven institutions for cfDNA measurements. Hot-spot mutations in KRAS and GNAS in the cfDNA from patients with PDA (n = 96), undergoing surveillance for IPMN (n = 112), and normal controls (n = 76) were evaluated using pre-amplification dPCR. Results Upon Qubit measurement and copy number Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00535-020-01724-5) contains supplementary material, which is available to authorized users.
assessment of hemoglobin-subunit (HBB) and mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) in plasma cfDNA, HBB offered the best resolution between patients with PDA relative to healthy subjects [area under the curve (AUC) 0.862], whereas MT-ND1 revealed significant differences between IPMN and controls (AUC 0.851). DPCR utilizing preamplification cfDNA afforded accurate tumor-derived mutant KRAS detection in plasma in resectable PDA (AUC 0.861–0.876) and improved post-resection recurrence prediction [hazard ratio (HR) 3.179, 95% confidence interval (CI) 1.025–9.859] over that for the marker CA19-9 (HR 1.464; 95% CI 0.674–3.181). Capturing KRAS and GNAS could also provide genetic evidence in patients with IPMNassociated PDA and undergoing pancreatic surveillance. Conclusions Plasma cfDNA quantification by distinct measurements is useful to predict tumor burden. Through appropriate methods, dPCR-mediated mutation detection in
& Yusuke Mizukami [email protected]
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Department of Pathology, Teine-Keijinkai Hospital, Sapporo, Japan
1
Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
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Department of Gastroenterology and Endoscopic Unit, Shibetsu City Hospital, Shibetsu, Japan
2
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University,
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