Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts
ABSTRACT OBJECTIVE: Pancreatic cysts are commonly detected in patients undergoing pancreatic imaging. Better approaches are needed to characterise these lesions. In this study we evaluated the utility of detecting mutant DNA in secretin-stimulated pancreatic juice. DESIGN: Secretin-stimulated pancreatic juice was collected from the duodenum of 291 subjects enrolled in Cancer of the Pancreas Screening trials at five US academic medical centres. The study population included subjects with a familial predisposition to pancreatic cancer who underwent pancreatic screening, and disease controls with normal pancreata, chronic pancreatitis, sporadic intraductal papillary mucinous neoplasm (IPMN) or other neoplasms. Somatic GNAS mutations (reported prevalence ∼66% of IPMNs) were measured using digital high-resolution melt-curve analysis and pyrosequencing. RESULTS: GNAS mutations were detected in secretin-stimulated pancreatic juice samples of 50 of 78 familial and sporadic cases of IPMN(s) (64.1%), 15 of 33 (45.5%) with only diminutive cysts (<5 mm), but none of 57 disease controls. GNAS mutations were also detected in five of 123 screened subjects without a pancreatic cyst. Among 97 subjects who had serial pancreatic evaluations, GNAS mutations detected in baseline juice samples predicted subsequent emergence or increasing size of pancreatic cysts. CONCLUSION: Duodenal collections of secretin-stimulated pancreatic juice from patients with IPMNs have a similar prevalence of mutant GNAS to primary IPMNs, indicating that these samples are an excellent source of mutant DNA from the pancreas. The detection of GNAS mutations before an IPMN is visible suggests that analysis of pancreatic juice has the potential to help in the risk stratification and surveillance of patients undergoing pancreatic screening.
- Journal of the American College of Surgeons 11/2014; 220(2). DOI:10.1016/j.jamcollsurg.2014.11.001 · 4.45 Impact Factor
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ABSTRACT: & Aims: Pancreatic imaging can identify neoplastic cysts but not microscopic neoplasms. Mutation analysis of pancreatic fluid following secretin stimulation might identify microscopic neoplasias in the pancreatic duct system. We determined the prevalence of mutations in KRAS and GNAS genes in pancreatic juice from subjects undergoing endoscopic ultrasound for suspected pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms, or pancreatic adenocarcinoma. Secretin-stimulated juice samples were collected from the duodenum of 272 subjects enrolled in Cancer of the Pancreas Screening studies; 194 subjects were screened because of a family history of, or genetic predisposition to, pancreatic cancer and 78 were evaluated for pancreatic cancer (n=30) or other disorders (controls: pancreatic cysts, pancreatitis, or normal pancreata, n=48 ). Mutations were detected by digital high-resolution melt-curve analysis and pyrosequencing. The number of replicates containing a mutation determined the mutation score. KRAS mutations were detected in pancreatic juice from larger percentages of subjects with pancreatic cancer (73%) or undergoing cancer screening (50%) than controls (19%) (P=.0005). A greater proportion of patients with pancreatic cancer had at least 1 KRAS mutation detected 3 or more times (47%) than screened subjects (21%) or controls (6%, P=.002). Among screened subjects, mutations in KRAS (but not GNAS) were found in similar percentages of patients with or without pancreatic cysts. However, a greater proportion of patients over 50 ys old had KRAS mutations (54.6%) than younger patients (36.3%) (P=.032); the older subjects also more mutations in KRAS (P=.02). Mutations in KRAS are detected in pancreatic juice from the duodenum of 73% of patients with pancreatic cancer, and 50% of asymptomatic individuals with a high risk for pancreatic cancer. However, KRAS mutations are detected in pancreatic juice from 19% of controls. Mutations detected in individuals without pancreatic abnormalities, based on imaging analyses, likely arise from small PanIN lesions. ClinicalTrials.gov no: NCT00438906 and NCT00714701. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.Clinical Gastroenterology and Hepatology 12/2014; 13(5). DOI:10.1016/j.cgh.2014.11.028 · 6.53 Impact Factor
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ABSTRACT: Evaluation of: Singhi AD, Nikiforova MN, Fasanella KE, et al. Preoperative GNAS and KRAS testing in the diagnosis of pancreatic mucinous cysts. Clin. Cancer Res. 20(16), 4381-9 (2014). Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have a risk of malignant transformation following an adenoma-carcinoma sequence. Surgical resection is often required, especially for main pancreatic duct IPMNs (MD-IPMNs). There is an urgent need for novel biomarkers to reliably differentiate IPMNs from more benign pancreatic cysts and therefore avoid unnecessary surgery. DNA sequencing has demonstrated that guanine nucleotide binding protein alpha stimulating (GNAS) activity polypeptide 1 mutations play a driving role in IPMN development. GNAS mutations have been shown to be highly specific for IPMNs, whereas oncogenic KRAS mutations have been associated with mucinous differentiation. The evaluated article by Singhi et al. helps to define the role of these mutations as biomarkers in preoperative endoscopic ultrasound fine-needle aspiration samples for detecting IPMNs. They found that the presence of a GNAS and/or a KRAS mutation was highly specific and sensitive for IPMNs.Expert Review of Molecular Diagnostics 02/2015; 15(3):1-4. DOI:10.1586/14737159.2015.1002771 · 4.27 Impact Factor