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- Title
Digital PCR-based plasma cell-free DNA mutation analysis for early-stage pancreatic tumor diagnosis and surveillance.
- 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
- 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 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.
- Subjects
DNA analysis; TUMOR diagnosis; BIOMARKERS; FORECASTING; CONFIDENCE intervals
- Publication
Journal of Gastroenterology, 2020, Vol 55, Issue 12, p1183
- ISSN
0944-1174
- Publication type
Article
- DOI
10.1007/s00535-020-01724-5