Methylation changes at the imprinted locus in pancreatic cystic neoplasms are important for the diagnosis of malignant cysts.

BACKGROUND

Guanine nucleotide-binding protein, alpha stimulating () mutations are characteristic of intraductal papillary mucinous neoplasms (IPMNs). Pancreatic ductal adenocarcinomas (PDACs) harboring mutations originate in IPMNs. is a complex imprinted locus that produces five transcripts regulated by differential methylated regions, , , , , and .

AIM

To evaluate if methylation changes in the differential methylated regions of GNAS locus contributed to malignant progression of pancreatic cysts.

METHODS

locus methylation was analyzed in archival pancreatic cyst fluid (PCF) obtained by endoscopic ultrasound with fine-needle aspiration by methylation specific-multiplex ligation dependent probe amplification. Results were normalized and analyzed using Coffalyser.Net software.

RESULTS

Fifty-two PCF samples obtained by endoscopic ultrasound with fine-needle aspiration and previously characterized for and mutations were studied. The final diagnoses were surgical (11) and clinicopathological (41), including 30 benign cysts, 14 pre-malignant cyst, and eight malignant cysts. Methylation changes at , and especially were more frequent in malignant cysts, and and were useful for diagnosis. A combined variable defined as " locus methylation changes" was significantly associated with malignancy (6/8 malignant cysts and only 2/20 benign cysts) and improved classification. Hypermethylation in both maternally () and paternally () derived promoters was found in 3/3 PDACs.

CONCLUSION

This is the first study to identify methylation changes in the locus, improving the diagnosis of malignant pancreatic cysts and suggesting a role in progression to PDAC.