Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia
Open accessAbstract
Objective: DNA-based testing of pancreatic cyst fluid (PCF) is a useful adjunct to the evaluation of pancreatic cysts (PCs). Mutations in KRAS/GNAS are highly specific for intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), while TP53/PIK3CA/PTEN alterations are associated with advanced neoplasia. A prospective study was performed to evaluate preoperative PCF DNA testing. Design: Over 43-months, 626 PCF specimens from 595 patients were obtained by endoscopic ultrasound (EUS)-fine needle aspiration and assessed by targeted next-generation sequencing (NGS). Molecular results were correlated with EUS findings, ancillary studies and follow-up. A separate cohort of 159 PCF specimens was also evaluated for KRAS/GNAS mutations by Sanger sequencing. Results: KRAS/GNAS mutations were identified in 308 (49%) PCs, while alterations in TP53/PIK3CA/PTEN were present in 35 (6%) cases. Based on 102 (17%) patients with surgical follow-up, KRAS/GNAS mutations were detected in 56 (100%) IPMNs and 3 (30%) MCNs, and associated with 89% sensitivity and 100% specificity for a mucinous PC. In comparison, KRAS/GNAS mutations by Sanger sequencing had a 65% sensitivity and 100% specificity. By NGS, the combination of KRAS/GNAS mutations and alterations in TP53/PIK3CA/PTEN had an 89% sensitivity and 100% specificity for advanced neoplasia. Ductal dilatation, a mural nodule and malignant cytopathology had lower sensitivities (42%, 32% and 32%, respectively) and specificities (74%, 94% and 98%, respectively). Conclusions: In contrast to Sanger sequencing, preoperative NGS of PCF for KRAS/GNAS mutations is highly sensitive for IPMNs and specific for mucinous PCs. In addition, the combination of TP53/PIK3CA/PTEN alterations is a useful preoperative marker for advanced neoplasia.
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Blood remains the most commonly studied biospecimen for early detection, but many analytes are also present in other proximate samples, including pancreatic juice, stool, urine, saliva, and pancreatic cyst fluid.
“In passing, it also needs to be stated that, although blood remains the most commonly studied biospecimen for early detection, many of the analytes are also present in other proximate samples, including pancreatic juice,53,54 stool,55 urine,56,57 saliva,58 and pancreatic cyst fluid.59”
From Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review (2021) · cites this paper as [59]
Preliminary studies evaluating PIK3CA, SMAD4, and TP53 mutations in cyst fluid identified almost 80% of intraductal papillary mucinous neoplasms with high-grade dysplasia or cancer.
“Preliminary studies evaluating the presence of mutations in PIK3CA, SMAD4, and TP53 in cyst fluid were promising, as they identified almost 80% of intraductal papillary mucinous neoplasms with high-grade dysplasia or cancer.43”
From Early detection of pancreatic cancer (2020) · cites this paper as [43]
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- Authors
- Singhi, A. D., McGrath, K., Brand, R. E., Khalid, A., Zeh, H. J., Chennat, J. S., Fasanella, K. E., Papachristou, G. I., Slivka, A., Bartlett, D. L., Dasyam, A. K., Hogg, M., Lee, K. K., Marsh, J. W., Monaco, S. E., Ohori, N. P., Pingpank, J. F., Tsung, A., Zureikat, A. H., Wald, A. I., & Nikiforova, M. N.
- Affiliations
- UPMC Health System (US)
- University of Pittsburgh (US)
- University of Pittsburgh Medical Center (US)
- Corresponding author
- Singhi, Aatur D
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2017-09-28
- Volume
- 67
- Issue
- 12
- Pages
- 2131-2141
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC6241612
- OpenAlex
- W2759917145
- Cited by
- 405
- References
- 32
- Citations by year
- 2026: 41 · 2025: 44 · 2024: 46 · 2023: 48 · 2022: 42 · 2021: 68 · 2020: 43 · 2019: 46 · 2018: 26 · 2017: 1
- FWCI
- 13.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Gut (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Pancreatic Cancer Action Network
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- pancreatic cysts, pancreatic cyst fluid, KRAS mutation, GNAS mutation, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, TP53, PIK3CA, PTEN, advanced neoplasia, endoscopic ultrasound-guided fine-needle aspiration, cyst classification, diagnostic accuracy
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Chromogranins, DNA, Neoplasm, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mutation, Neoplasm Proteins, Pancreatic Cyst, Pancreatic Neoplasms, Preoperative Care, Prospective Studies, Sensitivity and Specificity, Biomarkers, Tumor, Proto-Oncogene Proteins p21(ras), Neoplasms, Cystic, Mucinous, and Serous, GTP-Binding Protein alpha Subunits, Gs, Cyst Fluid, Carcinoma, Pancreatic Ductal, Young Adult, High-Throughput Nucleotide Sequencing, Endoscopic Ultrasound-Guided Fine Needle Aspiration
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