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

doi:10.4251/wjgo.v12.i9.1056

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World Journal of Gastrointestinal Oncology

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World J Gastrointest Oncol. Sep 15, 2020; 12(9): 1056-1064
Published online Sep 15, 2020. doi: 10.4251/wjgo.v12.i9.1056

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

Sandra Faias, Marlene Duarte, Luísa Pereira, Paula Chaves, Marília Cravo, Antonio Dias Pereira, Cristina Albuquerque

Sandra Faias, Antonio Dias Pereira, Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE, Lisboa 1099-023, Portugal

Sandra Faias, Paula Chaves, Faculty of Health Sciences, University of Beira Interior, Covilhã 6200-506, Portugal

Marlene Duarte, Cristina Albuquerque, Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE, Lisboa 1099-023, Portugal

Luísa Pereira, Centro de Matemática e Aplicações (CMA-UBI), Universidade da Beira Interior, Covilhã 6200-506, Portugal

Paula Chaves, Department of Pathology, Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE, Lisboa 1099-023, Portugal

Marília Cravo, Department of Gastroenterology, Hospital Beatriz Ângelo, Loures 2674-514, Portugal

Author contributions: All authors have contributed to the paper concept and design and agreed on the final content of the manuscript; Faias S, Duarte M, and Albuquerque C acquired and interpreted the data; Pereira L performed the statistical analysis; Faias S, Pereira L, Chaves P, Cravo M, and Albuquerque C drafted the manuscript under the supervision of both senior authors, Albuquerque C and Pereira AD; all authors critically revised the manuscript and approved the final version of the manuscript.

Supported by a Research Grant from Sociedade Portuguesa de Endoscopia Digestiva in 2018.

Institutional review board statement: The study was approved by the Ethics Committee and Institutional Scientific Board (UIC/1143).

Informed consent statement: All patients gave informed consent.

Conflict-of-interest statement: The authors have no conflicts of interest to disclose.

Data sharing statement: No additional data are available.

STROBE statement: Guidelines of STROBE statement have been adopted.

Corresponding author: Sandra Faias, MD, Attending Doctor, Research Fellow, Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE, Rua Prof Lima Basto, Lisboa 1099-023, Portugal. sandrarfaias@hotmail.com

Received: April 15, 2020
Peer-review started: April 15, 2020
First decision: July 5, 2020
Revised: July 18, 2020
Accepted: August 1, 2020
Article in press: August 1, 2020
Published online: September 15, 2020
Processing time: 147 Days and 18.2 Hours

Abstract

BACKGROUND

Guanine nucleotide-binding protein, alpha stimulating (GNAS) mutations are characteristic of intraductal papillary mucinous neoplasms (IPMNs). Pancreatic ductal adenocarcinomas (PDACs) harboring GNAS mutations originate in IPMNs. GNAS is a complex imprinted locus that produces five transcripts regulated by differential methylated regions, NESP55, GNASAS, GNASXL, GNAS1A, and GNAS.

AIM

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

METHODS

GNAS 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 KRAS and GNAS 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 NESP55, GNASAS, GNAS1A, and especially GNASXL were more frequent in malignant cysts, and NESP55 and GNASAS were useful for diagnosis. A combined variable defined as “GNAS 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 (NESP55) and paternally (GNASXL) derived promoters was found in 3/3 PDACs.

CONCLUSION

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

Keywords: Intraductal papillary mucinous neoplasms; Pancreas cyst; Methylation; Biomarker; GNAS locus; Pancreatic neoplasm

Core Tip: Pancreatic cystic lesions are a clinical dilemma due to risk of malignancy. Somatic mutations of guanine nucleotide-binding protein, alpha stimulating (GNAS) are characteristic of intraductal papillary mucinous neoplasms. We found methylation changes in differential methylated regions at the GNAS locus in pancreatic cyst fluid predominantly of malignant cysts. Methylation changes in GNAS locus may improve the diagnosis of malignant cysts and shed light on the development of novel therapeutic approaches for pancreatic cancer.