Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing.

Autor:	Majumder S; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Taylor WR; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Yab TC; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Berger CK; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Dukek BA; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Cao X; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Foote PH; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Wu CW; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Mahoney DW; Department of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, Minnesota, USA., Aslanian HR; Yale University, New Haven, Connecticut, USA., Fernández-Del Castillo C; Massachusetts General Hospital, Boston, Massachusetts, USA., Doyle LA; Brigham and Women's Hospital, Boston, Massachusetts, USA., Farrell JJ; Yale University, New Haven, Connecticut, USA., Fisher WE; Baylor College of Medicine, Houston, Texas, USA., Lee LS; Brigham and Women's Hospital, Boston, Massachusetts, USA., Lee YN; Stanford Heath Care, Palo Alto, California, USA., Park W; Stanford Heath Care, Palo Alto, California, USA., Rodrigues C; Massachusetts General Hospital, Boston, Massachusetts, USA., Gould Rothberg BE; Yale University, New Haven, Connecticut, USA., Salem RR; Yale University, New Haven, Connecticut, USA., Simeone DM; University of Michigan, Ann Arbor, Michigan, USA., Urs S; University of Michigan, Ann Arbor, Michigan, USA., Van Buren G; Baylor College of Medicine, Houston, Texas, USA., Smyrk TC; Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota, USA., Allawi HT; Exact Sciences Corporation, Madison, Wisconsin, USA., Lidgard GP; Exact Sciences Corporation, Madison, Wisconsin, USA., Raimondo M; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Chari ST; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Kendrick ML; Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA., Kisiel JB; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Topazian MD; Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Ahlquist DA; Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL.
Jazyk:	angličtina
Zdroj:	The American journal of gastroenterology [Am J Gastroenterol] 2019 Sep; Vol. 114 (9), pp. 1539-1549.
DOI:	10.14309/ajg.0000000000000284
Abstrakt:	Objectives: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). Methods: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. Results: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). Discussion: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.
Databáze:	MEDLINE
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