Novel Methylated DNA Markers May Detect Advanced Neoplasia in Pancreatic Cysts

View into a pancreatic pseudocyst through the posterior wall of the stomach.
In an analysis of pancreatic tissue and cyst fluid samples, researchers identified and validated DNA methylation makers that can detect advanced neoplasia.

Novel methylated DNA markers (MDMs) assayed from cyst fluid can accurately detect advanced neoplasia in pancreatic cystic lesions (PCLs), according to a study published in The American Journal of Gastroenterology.

PCLs likely to harbor pancreatic cancer or high-grade dysplasia are targets for surgical resection, but current algorithms to predict pancreatic cancer and high-grade dysplasia in PCLs lack diagnostic accuracy. The current study tested cyst fluid and pancreatic tissue from PCLs to identify and validate novel MDMs that can discriminate pancreatic cancer/high-grade dysplasia from no dysplasia or low-grade dysplasia.

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Using predefined selection criteria followed by a multistep validation on case (pancreatic cancer or high-grade dysplasia) and control (low-grade dysplasia or no dysplasia) tissues in an unbiased whole-methylome discovery approach, investigators identified discriminant MDMs. Top candidates were then assayed on archival cyst fluid taken from surgically resected PCLs using a quantitative methylation-specific polymerase chain reaction.

Of the 25 discriminant MDMs identified, investigators selected 13 for validation in 134 samples of cyst fluid (21 cases [8 high-grade dysplasia, 13 pancreatic cancer] and 113 controls [45 no dysplasia, 68 low-grade dysplasia]). A tree-based algorithm using 2 cyst fluid-MDMs (TBX15, BMP3) achieved an area under the curve of 0.93 (95% CI, 0.86-0.99) with a sensitivity of 90% (95% CI, 70%-99%) and a specificity of 92% (95% CI, 85%-96%).

Discrimination by this cyst fluid-MDM panel (areas under the receiver operating characteristic curve, 0.93; 95% CI, 0.86-0.99) was significantly better (P <.007) than discrimination by mutant KRAS (0.71; 95% CI, 0.57-0.85) or carcinoembryonic antigen (0.72; 95% CI, 0.60-0.84). MDM panel cutoffs applied to an independent cyst fluid validation set of 31 cases and 56 controls yielded similarly high discrimination (areas under the receiver operating characteristic curve, 0.86; 95% CI, 0.77-0.94; P =.2).

Study limitations included the use of archived samples that were collected with varying protocols from multiple centers, and histologic diagnosis was not subjected to a centralized pathology review.

Study investigators concluded that “our study demonstrates that novel DNA methylation markers assayed from [cyst fluid] can accurately detect advanced neoplasia in PCLs. Prospective studies are currently underway to include patients assigned to both immediate surgery and clinical follow-up arms in an attempt to corroborate these findings and optimize marker combinations for clinical use.”

Disclosure: Graham P. Lidgard, PhD, and Hatim T. Allawi, PhD, are employees of Exact Sciences.


Majumder S, Taylor WR, Yab TC, et al. Novel methylated DNA markers discriminate advanced neoplasia in pancreatic cysts: Marker discovery, tissue validation, and cyst fluid testing [published online July 15, 2019]. Am J Gastroenterol. doi:10.14309/ajg.0000000000000284