Digital PCR-based plasma cell-free DNA mutation analysis for early-stage pancreatic tumor diagnosis and surveillance

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...

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Bibliographic Details
Published in:Journal of gastroenterology 2020-12, Vol.55 (12), p.1183-1193
Main Authors: Okada, Tetsuhiro, Mizukami, Yusuke, Ono, Yusuke, Sato, Hiroki, Hayashi, Akihiro, Kawabata, Hidemasa, Koizumi, Kazuya, Masuda, Sakue, Teshima, Shinichi, Takahashi, Kuniyuki, Katanuma, Akio, Omori, Yuko, Iwano, Hirotoshi, Yamada, Masataka, Yokochi, Tomoki, Asahara, Shingo, Kawakubo, Kazumichi, Kuwatani, Masaki, Sakamoto, Naoya, Enomoto, Katsuro, Goto, Takuma, Sasajima, Junpei, Fujiya, Mikihiro, Ueda, Jun, Matsumoto, Seiji, Taniue, Kenzui, Sugitani, Ayumu, Karasaki, Hidenori, Okumura, Toshikatsu
Format: Article
Language:English
Subjects:
Abdominal Surgery
Adenocarcinoma
Biliary Tract
Cancer
Colorectal Surgery
Copy number
Deoxyribonucleic acid
Diagnosis
DNA
Gastroenterology
Gene mutations
Genetic aspects
Genetic research
Hemoglobin
Hepatology
Invasiveness
Medical diagnosis
Medicine
Medicine & Public Health
Mitochondria
Mutation
Mutation hot spots
NADH
NADH-ubiquinone oxidoreductase
Original Article—Liver
Pancreas
Pancreatic cancer
Plasma
Polymerase chain reaction
Surgical Oncology
Surveillance
Tumors
Ubiquinone
Ubiquinone oxidoreductase
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Summary: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 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 pre-amplification 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 IPMN-associated 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 patients with localized PDA and IPMN likely to progress to invasive carcinoma is feasible and complements conventional biomarkers.
ISSN:0944-1174
1435-5922
DOI:10.1007/s00535-020-01724-5